JP2001512132A - Lixofuranosylbenzimidazole as an antiviral drug - Google Patents

Abstract

(57) Abstract The present invention relates to D- and L-lyxofuranosylbenzimidazole compounds. In one aspect, the present invention provides a compound of the following formula: (Wherein, R ² , R ⁴ , R ⁵ , R ⁶ and R ⁷ are the same or different, and independently represent —H, —F, —Cl, —Br, —I, —NO ₂ , — N (R ⁸⁾ _2, are independently selected from the group consisting of -OR ^8, -SR ¹² and -CF _3, alkyl having or 6 carbon atoms R ⁸ is independently -H R ¹² is independently —H or a hydrocarbyl group having 1 to 10 carbon atoms, and R ⁹ , R ¹⁰ and R ¹¹ are each the same or different and are H Or a compound having the formula selected from: or a hydroxyl protecting group, selected from the group consisting of anomeric, optical, and conformational isomers thereof, and pharmaceutically acceptable salts and prodrug derivatives thereof. D- or L-Lixofuranosylben Imidazole compounds, related. The present invention also relates to antiviral compositions using these compounds, methods of treating viral infections using these compounds, and the use of these compounds in the preparation of a medicament for use in treating viral infections.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD BACKGROUND OF THE INVENTION This invention generally field of benzimidazole nucleoside analogues and their use as antiviral agents. More specifically, the present invention relates to benzimidazole nucleoside analogs in which the sugar group is a lyxofuranosyl group and derivatives thereof. The invention also relates to methods of making such benzimidazole nucleoside analogs and derivatives, compositions comprising these compounds, and the use of these compounds in antiviral therapy.

[0002] In the context the present application, publication, such patents and patent application publication specification, various publications, but not limited to, represents the confirmation of the quote. The disclosures of these references, such as publications, patent specifications, and patent application publications, cited in the present application are:
Reference is made to this disclosure by reference to describe the state of the art to which this invention pertains in more detail.

[0003] Microorganisms of the Herpesviridae family have a common virion structure. A typical herpes virion consists of (a) a core containing two linear DNAs, (b)
An icosahedral capsid with a diameter of about 100-120 nm containing 162 capsomers, (c) an amorphous, possibly asymmetrical material called a segment surrounding the capsid, and (d) a viral glycoprotein spike on the surface. Consisting of an envelope.

[0004] The major examples of human pathogens of the herpesviridae family include herpes simplex virus (HSV) types 1 and 2, and the ring-tailed herpesvirus 1 (B-virus), varicella-zoster (varicella and shingles). Causing herpes), Epstein-
Barr virus (EBV, causing mononucleosis), human herpes virus 6 (H
HV6), human herpesvirus 7 (HHV7) and caposi-associated herpesvirus (KHV), or human herpesvirus 8 (HHV8). This is also a human herpes virus, human cytomegalovirus (HCM
V) is an individual with suppressed immunity (Alford, CA, Britt. WJ Cytomegalovirus) / "The Human Herpesvirus",
See Roizman, B., Whitley, RJ, Lopez, C. (supervised), Raven Press, New York, 1993, pp. 227-255) and newborns (Alford, CA, Stagon, S.).
, Pass, RF, Brit, WJ "Congenital and Perinatal Cytomegalovirus Infections i
n Bone Marrow Transplants), Rev. Infect. Dis. 1990, 12, s793-s804, and Gallant, JE, Moore, RD, Richman, DD Keruly, J., Chaisson, RE Incidence and Natural History of Cytomegalovirus Disease in Patients with Deficiency Virus Disease
Cytomegalovirus Disease in Patients with Advanced Immunodeficiency Virus
Disease Treated with Zidovudine) ", J. Infect. Dis. 1992, 166, 1223-122.
7) are the major opportunistic pathogens.

[0005] Animal pathogens include bovine rhinotracheitis virus, bovine papillitis virus, and ring-tailed herpesvirus type 1 (B-virus), all of which are simple viruses, and pseudorabies virus (PRV, pig) , Equine rhinopneumonia and dorsal herpes virus (varicella virus), baboon herpes virus, orangutan (chimpanzee) herpes virus (lymphoid virus), Marek second virus (avian), turkey herpes virus, spider monkey herpes virus and squirrel herpes virus (
Radinovirus). For a review, see Murphy et al., Virus Taxonomy / Fields et al.
tal Virology), 1991, New York, pp. 9-36; Watson et al. "Molecular Biology of the Gene", 4th edition, 1987, Benja
See min / Cummings Publ. Co., Menlo Park, California, pages 904,933.

[0006] The herpesvirus genome, generally 120-230 kb in length, encodes 50-200 different proteins. These include the metabolism of nucleic acids (eg, thymidine kinase, thymidylate synthetase, dUTPase, ribonucleotide reductase, etc.), and DNA synthesis (eg, DNA polymerase, helicase,
Primase).

[0007] In herpes virus, the linear genome is characterized by a repetitive sequence, which comprises a number,
It varies in length and arrangement between various types of herpes viruses. For example, Epst
In the ein-Barr virus, at both ends of the genome there are a number of short (500 base pairs) repeats of the same sequence as well as an internal sequence consisting of six repeats of the 3 kb sequence. In herpes simplex virus types 1 and 2, and HCMV, a part of the sequence from both ends is repeated inside and juxtaposed in reverse orientation, dividing the genome into two components, each of which is a unique sequence flanked by inverted repeats. Consists of In this case, both components (long (L) arm and short (S) arm) may be reversed. DNA extracted from virions or infected cells consists of four equimolar individuals with different relative orientation of the two components. For a review, see Watson et al. 1987, p. 935; Roizman, Herpesvirus.
: Herpesviridae: A Brief Introduction / Fields et al.
Fundamental Virology, 1991, Raven Press, New York, pp. 841-847; Roizman et al., Herpes Simplex Viruses and Their Replication / Fields et al. ), "Fundamental Virology", 1991, Raven Press, New York, pp. 849-895.

[0008] To initiate infection, the virus binds to a receptor on the host cell. Fusing of the viral envelope with the plasma membrane initiates rapid binding. The de-enveloped capsid is then transported to the nuclear pore, where the DNA is released to the nucleus and rapidly cyclizes. In the next step, transcription and translation of the herpes gene is tightly regulated. Three types of genes are known, α, β and γ (or very early,
Early and late). The expression of the α gene is necessary for the expression of the β gene, and the expression of the β gene induces the γ gene, stops the α gene, and stops the β gene by expression of the γ gene. Thus, during replication, there are three different waves of herpesvirus gene expression. Interestingly, this step appears to be cyclic in that at least one virion protein (γ gene product) is required for induction of gene expression immediately after infection. This product facilitates the start of the cycle by entering with the virions. For a review, Wa
tson et al. 1987, p. 935-936; Roizman et al., Herpes Simplex Viruses and Their Replication / Fields et al.
(Supervision) "Fundamental Virology", 1991, Raven Pres
s, New York, pp. 849-895.

[0009] Some herpes viruses, such as HSV-1 and HSV-2, have a broad host cell range, proliferate efficiently, and rapidly destroy infected cells. Other viruses (eg, EBV, HHV6) have a narrow host cell range or, in the case of HCMV, replicate slowly. For a review, see Roizman et al., Herpes Simplex Viruses and Their Replication / Fi
elds et al. (supervision) "Fundamental Virology", 1991,
See Raven Press, New York, pp. 849-895.

[0010] Herpes virus replicates in the cell nucleus, nucleoli migrates, degrades and then breaks down, leading to marginalization of the host chromosome, which can destroy the chromosome. Host protein synthesis is reduced very quickly (for most herpes viruses except HCMV), host ribosomal RNA synthesis is reduced, and glycation of host proteins is stopped. Progeny production necessarily involves irreversible destruction of infected cells. For a review, see Roizman et al., Herpes Simplex Viruses and Their Replication (Herpes
(Simplex Viruses and Their Replication) / Fields et al. (Supervision) "Fundamental Virology", 1991, Raven Press, New York, 8
See pages 49-895.

[0011] Various disease symptoms and complex clinical courses are caused by the herpes virus. If a human adult is first infected, the symptoms can be quite severe. Herpesviruses can cause repeated infections, and injury from these relapses is a serious health problem. The most common manifestations of recurrent herpes disease were disclosed to involve the orofacial and genital areas, and recurrent herpetic keratitis was listed as the leading cause of blindness in the United States. Herpes genital infections, which subsequently have a high incidence of recurrent disease, have been noted as being more prevalent and responsible for significant morbidity.
Cohen et al., U.S. Patent No. 4,709,011, November 24, 1987.
Issued daily.

[0012] In studying the molecular basis of HSV-induced disease, the goal of the study—the disease—may be synonymous with destruction of the central nervous system (CNS). However, the virus may initially grow in peripheral locations to spread to target organs. In an experimental system, neural virulence, a model for diseases that produce the phenotype of HSV, is the result of (i) proliferation in the periphery, (ii) invasion of the CNS, and (iii) growth in the CNS. Virulence sites have been particularly reduced to several sites in the HSV genome except in or around the domain of the tk gene and at one end of the L portion. However, HSV
Almost every mutation or deletion in the genome reduces virulence. For a review, see Roizman et al., Herpes Simplex Viruses and Their Replication / Fields et al. (Supervised) "Fundamental Virology", 1991, Raven Press, New York, See pages 849-895.

[0013] In the case of EBV and HCMV, acute hepatitis is often due to infectious mononucleosis. Mononuclear cells are major candidates for cells involved in the latent state of HCMV, and infectious mononucleosis can result from transfusion from seropositive to seronegative humans. Seronegative humans can also be infected by transplantation of cells or organs from seropositive donors. For a review, Ah
med et al., Virus Persistence / Fields et al.
Fundamental Virology ", 1991, Raven Press, New York, pp. 241-265; Stinski, cytomegalovirus and its replication (Cy
See Tomegalovirus and its Replication / Fields et al. (supervised) "Fundamental Virology", 1991, Raven Press, New York, pp. 929-950.

The herpesviruses of economic importance in animal husbandry are bovine herpesvirus type 1 (BHV-1), and various herpes such as rhinotracheitis, vulvar vaginitis, miscarriage, conjunctivitis, encephalitis and systemic infections. Was involved in the development of clinical disease. Gibbs et al., 1977,
Bovine Herpesvirus I: Bovine Herpesvirus 1
Bovine herpesvirus-1), Vet. Bull. (London) 47: 317-343.

[0015] Pseudora, a herpes virus also called Aujeszky disease virus (ADV)
The bies virus (PRV) is a disease of all livestock except horses and causes severe damage, especially to pigs and cattle. Pigs are the natural host of ADV. Animals are infected nasally, and after primary virus growth in the mucous membranes of the upper respiratory tract and gastrointestinal tract, the virus propagates through the nerves to the brain. The infection progresses rapidly asymptomatically, and varies mainly with viral virulence and pig age. PRV, like other herpesviruses, induces latent infections, ie, infections in neural tissue.
Berns et al., US Pat. No. 4,680,176, issued Jul. 14, 1987.

At present, only three drugs are approved by the FDA for the treatment of HCMV infection: Crumpacker, CS Ganciclovir
clovir), New England J. Med. 1996, 335, 721-729), foscarnet (
Chrisp, P., Clissold, SP Foscal net. A review of its Antiviral Activity, Pharmacokinetic Prope, and its antiviral activity, kinetic properties, and therapeutic use in immunocompromised patients with cytomegalovirus retinitis
rties and Therapeutic Use in Immunocompromised Patients with Cytomegalov
irus Retinitis), Drugs 1991, 41, 104-129), Sidfibre (Hitchcoc)
k, MJ, Jaffe, HS, Martin, JC, Stagg, RJ, Cidofovir, a new drug with potent anti-herpesvirus activity (Cidofovir, a new agent with poten
t anti-herpesvirus activity), Antiviral Chem. & Chemother. 1996, 7: 115-
127. (b) Lalezari, JP, Drew, WL, Glutzer, E., James, C., Miner, D.,
Flaherty, J. Fisher, PE, Cundy, K., Hannigan, J., Martin, JC, Jaffe,
HS, (S) -1- [3-Hydroxy-2- (phosphonylmethoxy) propyl] cytosine (Cidofovir): Results of a phase I / II study of a novel antiviral nucleotide analogue ((S) -1- [3-hydroxy-2- (phosphonylmethoxy) propyl] cytosine
(Cidofovir): Results of a Phase I / II Study of a Novel Antiviral Nucleoti
de Analogue), J. Infect. Dis. 1995, 171, 788-796). All of these drugs can cause side effects such as renal dysfunction (foscarnet and sidfivir) and granulocytopenia (ganciclovir). In addition, potential drug resistance and poor oral bioavailability require more potent and selective drugs (Field, AK, Biron, KK, The End of I
nnocence) '' Revised: Resistance of Herpesvirus to Antiviral Drugs (Resistance of
Herpesviruses to Antiviral Drugs), Clin. Microbiol. Rev. 1994, 7, 1-13).

Recent work by the inventors on novel antiviral drugs against herpes virus has focused on halogenated benzimidazole analogs. This type of compound was first reported in 1954 (Tamm, I., Folkers, K., Shunk, CH, Horsfall, F.
L., Jr. Inhibition of Influenza Virus Multiplication by N-Glycosides
of Benzimidazoles), J. Exp. Med. 1954, 99, 227-250), and 5,6-dichloro-1- (β-D-ribofuranosyl) benzimidazole (DRB) Reported as the most active antiviral compound in the series. Unfortunately, DRB was subsequently found to affect multiple cellular processes, and thus little activity was separated from its cytotoxicity (
Bucknall, The Effects of Substituted Benzimidazoles on the Grow on Virus Growth and Nucleic Acid Metabolism in Host Cells
th of Viruses and the Nucleic Acid Metabolism of Host Cells), J. Gen. Vi
rol. 1967, 1, 89-99. (b) Tamm, I., Sehgal, PB Halobenzimidazole Ribosides
nd RNA Synthesis of Cells and Viruses), Adv. Virus Res. 1978, 22, 187-25
8).

[0018]

Embedded image "DRB" 1- (β-D-ribofuranosyl) -5,6-dichloro-benzimidazole

Next, the synthesis of several heterocyclic modified DRB analogs has been reported (
Townsend, LB, Revankar, GR Benzimidazole Nucleosides, Nucleotides, and Relatkar
ed Derivatives) Chem. Reviews 1970, 70: 389-438). Of these, 2-substituted-5,6-dichloro-benzimidazole ribonucleosides were found to be the most potent (Townsend, LB, Devivar, RV, Turk, ST, Nassiri, M. et al.
R., Drach, JC Design, synthesis and antiviral activity of certain 2,5,6-trihalo-1- (β-D-ribofuranosyl) benzimidazoles
sis, and Antiviral Activity of Certain 2,5,6-Trihalo-1- (β-D-ribofuranos
yl) benzimidazoles) J. Med. Chem. 1995, 38, 4098-4105; Zou, R., Ayres, K.
R., Drach, JC Townsend, LB Synthesis and antiviral activity of certain disubstituted benzimidazole ribonucleosides
Certain Disubstituted Benzimidazoles) J. Med. Chem. 1996, 39, 3477-3482;
Zou, R. Drach, JC, Townsend, LB, Design and synthesis of 2-chloro-5,6-dihalo-1-β-D-ribofuranosylbenzimidazole as a potential drug for human cytomegalovirus infection. And antiviral activity evaluation (Design, Syn
thesis, and Antiviral Evaluation of 2-Chloro-5,6-dihalo-1-β-D-ribofuran
osylbenzimidazoles as Potential Agents for Human Cytomegalovirus Infecti
ons) J. Med. Chem. 1997, 40, 811-818; and Zou, R., Drach, JC, Townse.
nd, LB Design, synthesis and antivirus of 2-substituted 4,5-dichloro- and 4,6-dichloro-1-β-D-ribofuranosylbenzimidazoles as potential agents for human cytomegalovirus infection Evaluation of activity (Design, Synthesis
, and Antiviral Evaluation of 2-Substituted 4,5-Dichloro- and 4,6-Dichlo
ro-1-β-D-ribofuranosylbenzimidazoles as Potential Agents for Human Cyto
megalovirus Infections) J. Med. Chem. 1997, 40, 802-810). For example, 2,5,6-trichloro-1- (β-D-ribofuranosyl) benzimidazole (TCRB) and 2-bromo-5,6-dichloro-1- (β-D-ribofuranosyl) benzimidazole (BDCRB) Has been shown to be an important inhibitor of HCMV and this activity was completely separated from its cytotoxicity (Townsend, LB, De
vivar, RV, Turk, ST, Nassiri, MR, Drach, JC Certain 2,5,6-
Synthesis and antiviral activity of trihalo-1- (β-D-ribofuranosyl) benzimidazole and antiviral activity of Certain 2,5,6-Trihalo-
1- (β-D-ribofuranosyl) benzimidazoles) J. Med. Chem. 1995, 38, 4098-4105).

[0020]

Embedded image 1- (β-D-ribofuranosyl) -2,5,6-trichloro-benzimidazole

[0021]

Embedded image "BDCRB" 1- (β-D-ribofuranosyl) -2-bromo-5,6-dichloro-benzimidazole

In addition, several 2-alkylthio- and 2-benzylthio analogs have been prepared (Devivar, RV, Kawashima, E., Revankar, GR, Breitenbach, JM,
Kreske, ED, Drach, JC, Townsend, LB Benzimidazole ribonucleoside: certain 2- (alkylthio)-and 2- (benzylthio) -5,6-
Design, synthesis, and antiviral activity of dichloro-β-D-ribofuranosyl) benzimidazole (Ribonucleosides: Design, Synthesis, and antiviral Activ
ity of Certain 2- (Alkylthio)-and 2- (Benzylthio) -5,6-dichloro-β-D-ribof
uranosyl) benzimidazoles) J. Med. Chem. 1994, 37, 2942-2948).

In addition to these D-carbohydrate derivatives, several carbocycles (Townsend, LB, Drac
h, JC, Good, SS, Daluge, SM, Martin, MC Therapeutic nucleoside (Thera
peutic Nucleosides), U.S. Pat. No. 5,534,535 issued 7/9/96), and L-carbohydrates (Koszalka, GW, Chamberlain, SD, Daluge, S.P.
.M., Boyd, FL, Tidwell, JH, Martin, MT, Harvey, RJ, Frick, LW,
Perkins, DC, Wang, LH, Drach, JC, Townsend, LB, Biron, KK Benzimidazole for the treatment of human cytomegalovirus infection
les for the treatment of human cytomegalovirus infection / The 2nd International Conference: Nucleosides, Nucleotides, and Their Biological Applications (In XII Intern)
ational Roundtable: Nucleosides, Nucleotides and their Biological Applic
ations), La Jolla, California, September 1996). Derivatives have been synthesized and evaluated.

[0024]

Embedded image 1- (β-L-rifofuranosyl) -2-isophenylamino-5,6-dichloro-benzene imidazole

The present invention relates to a new class of benzimidazole nucleoside analogues in which the sugar group is a lixofuranosyl group or a derivative thereof.

[0026]

Summary of the Invention

SUMMARY OF THE INVENTION One aspect of the present invention relates to D- and L-lyxofuranosylbenzimidazole compounds. In one aspect, the present invention provides:

[0027]

Embedded image (Wherein R ² , R ⁴ , R ⁵ , R ⁶ and R ⁷ are the same or different,
Independently -H, -F, -Cl, -Br, -I, -NO 2, -N (R 8) 2, are independently selected from the group consisting of -OR ^8, -SR ¹² and -CF ₃ Wherein, R ⁸ is independently —H or an alkyl group having 1 to 6 carbon atoms (methyl,
Such as ethyl, propyl, isopropyl, and cyclopropyl), and R ¹² is independently —H or a hydrocarbyl group having 1 to 10 carbon atoms (aliphatic, cycloaliphatic and aromatic groups, for example, Alkyl, aryl, aralkyl,
R ⁹ , R ¹⁰ and R ¹¹ are each the same or different and are H or a hydroxyl-protecting group (eg, acetyl). D- or L-lyxofuranosylbenzimidazole compounds selected from the group consisting of: anomers, optical and conformers, and pharmaceutically acceptable salts and prodrug derivatives thereof.

In one aspect, the invention relates to D- and L-lyxofuranosylbenzimidazoles
Compound (wherein, R²Is -H, -F, -Cl, -Br, -I and -N (R⁸)₂ Selected from the group consisting of^FourAnd R⁷Are both -H and R⁵And R ⁶ Are independently the same or different and are selected from the group consisting of -H, -F, -Cl, -Br and -I), their anomers and optical isomers, their chemical
Protected forms, and their pharmaceutically acceptable salts and prodrug derivatives
About the body.

In one aspect, the present invention relates to α-D-lyxofuranosylbenzimidazole compounds. In one aspect, the invention relates to β-D-lyxofuranosylbenzimidazole compounds. In one aspect, the present invention relates to α-L-lyxofuranosylbenzimidazole compounds. In one aspect, the invention relates to β-L-lyxofuranosylbenzimidazole compounds.

In one embodiment, the present invention relates to 1- (lixofuranosyl) -2,5,6-trichloro-benzimidazole, 1- (lixofuranosyl) -2-bromo-5,6-dichloro-benzimidazole, 1- ( Lixofuranosyl) -2-methylamino-5,6-dichloro-benzimidazole, 1- (lixofuranosyl) -2-isopropylamino-5,6-dichloro-benzimidazole, 1- (lixofuranosyl) -2-cyclopropylamino-5 1,6-dichloro-benzimidazole, 1- (lixofuranosyl) -2-thio-5,6-dichloro-benzimidazole, 1- (lixofuranosyl) -2-benzylthio-5,6-dichloro-benzimidazole, 1- ( Lixofuranosyl) -2-methylthio-5,6-dichloro-benzimidazole, its anomer, optical and conformational isomers And pharmaceutically acceptable salts and prodrug derivatives thereof selected from the group consisting of, D- and L- Li shit Furano Shiruben's imidazole compounds, related.

Compounds not encompassed by the present invention include 1- (5′-deoxy-lixofuranosyl) -2,5,6-trichloro-benzimidazole, 1- (5′-deoxy-lixofuranosyl) -2-bromo- 5,6-dichloro-benzimidazole, and 1- (5'-deoxy-lixofuranosyl) -2-isopropylamino-5,6-dichloro-benzimidazole.

Another aspect of the invention relates to a composition comprising a biologically acceptable carrier and a D- or L-lyxofuranosylbenzimidazole compound of the invention. In one aspect, the carrier can be a pharmaceutically acceptable carrier as defined in the art.

Another aspect of the present invention relates to inhibiting viral replication and growth by contacting the virus with a D- or L-lyxofuranosylbenzimidazole compound of the present invention.

[0034] Yet another aspect of the invention is that an infected host is treated with a therapeutically effective amount of an antiviral lixofuranosylbenzimidazole compound of the invention, alone or with a carrier, such as a pharmaceutically acceptable carrier. A method of treating and / or preventing a viral infection comprising administering in combination.

Another embodiment of the present invention provides a method wherein the virus is combined with a therapeutically effective amount of an antiviral lyxofuranosylbenzimidazole compound of the present invention, alone or in combination with a carrier, such as a pharmaceutically acceptable carrier. A method of treating and / or preventing a hepatitis virus infection, such as hepatitis B and C, comprising contacting.

[0036] Yet another aspect of the present invention relates to the use of a D- or L-lyxofuranosylbenzimidazole compound of the present invention in the manufacture of a medicament for use in the treatment of a viral infection.

[0037] Still another aspect of the present invention relates to a method for producing the D- or L-lyxofuranosylbenzimidazole compound of the present invention.

As will become apparent, the preferred features and characteristics of one aspect of the invention are applicable to any other aspect of the invention.

[0039]

DETAILED DESCRIPTION OF THE INVENTION

DETAILED DESCRIPTION OF THE INVENTION Antiviral Compounds of the Present Invention The antiviral compounds of the present invention are benzimidazole nucleoside analogs comprising a benzimidazole group attached to the sugar group Q via position 1.

[0040]

Embedded image

The term “sugar group” as used herein relates to sugar groups in cyclic form, such as those derived from furanoses (5-membered rings). Examples of sugar groups include treoflanosyl (derived from threose, tetracarbon sugar), ribofuranosyl (derived from ribose, pentose),
Examples include aflafuranosyl (often called arabinofuranosyl; derived from arabinose, pentose) and xylofuranosyl (derived from xylose, pentose). Examples of these sugars are shown below.

[0042]

Embedded image

More specifically, the compound of the present invention comprises a benzimidazole group linked via a 1-position to the 1′-position of a lixofuranosyl group (or a derivative thereof).
Rikusofuranoshiru is, 2'-OH, 3'-OH and _4'-CH 2 OH is characterized in that on the same side as the furanosyl plane. In this method, lixofuranosyl and ribofuranosyl are often referred to as 4'-epimers because the pair differs in the 4'-carbon configuration.

As used herein, the term “benzimidazole” refers to 2-, 4-, 5-, 6
- relates to 1 or ^{R 2, R 4, R 5} , with R ⁶ and R ⁷ may be substituted independently as shown below, respectively benzimidazol-1-yl group 7-position.

[0045]

Embedded image

Examples of benzimidazole substituents R ² , R ⁴ , R ⁵ , R ⁶ and R ⁷ include-
H, halogen (e.g., -F, -Cl, -Br, -I ), - NO 2, -NR 2 (
Wherein R is independently -H or an alkyl group having 1 to 6 carbon atoms), -OR (where R is -H, or 1 to 6 an alkyl group having a carbon atom), - SR (wherein, R is either a -H, or from 1 to 10 hydrocarbyl groups having carbon atoms), and -CF ₃ and the like.

Examples of benzimidazole groups include halobenzimidazoles such as halo-, dihalo-, trihalo-, tetrahalo-, and pentahalobenzimidazole, eg, 2,5,6-trihalobenzimidazole (eg, 2, 5,6-trichlorobenzimidazole, 2-bromo-5,6-dichlorobenzimidazole, 2,4,6-trihalobenzimidazole (for example, 2,4,6-trichlorobenzimidazole, 2-bromo-4,6 -Dichlorobenzimidazole),
2,4,5,6-tetrahalobenzimidazole (eg, 2,4,5,6-tetrachlorobenzimidazole, 2-bromo-4,5,6-trichlorobenzimidazole), but are not limited thereto. Not done. Other examples of benzimidazole groups include 2-substituted-4,5-dihalobenzimidazoles (e.g., 2-
Amino-4,5-dichlorobenzimidazole, 2-isopropylamino-4,
5-dichlorobenzimidazole, 2-methoxy-4,5-dichlorobenzimidazole, 2-trifluoromethyl-4,5-dichlorobenzimidazole). Many benzimidazole compounds and methods for making them are known in the art. For example, U.S. Patent Nos. 5,248,672 and 5,3
See 60,795.

In one embodiment of the present invention, the benzimidazole group is a 5,6-dichlorobenzimidazole group. In another aspect of the invention, the benzimidazole group is a 2,5,6-trichlorobenzimidazole group. In a further aspect of the present invention, benzimidazole group is a 2-substituted-5,6-dichloro-benzimidazole group, wherein the 2 substituents is an amino group (i.e., _-NH 2),
Substituted amino groups (e.g., -NHR, N (R) ₂ , wherein R is an alkyl group having 1-6 carbon atoms), halo groups (e.g., -F, -Cl, -Br, -I)
, A sulfhydryl group (ie, -SH) or a thioether group (ie, -S
R (where R is a hydrocarbyl group having 1-10 carbon atoms)

Examples of compounds of the present invention include those listed below, and their anomeric (ie, α- and β-) and optical (ie, D- and L-) isomers, and their pharmaceutically acceptable Salts and prodrug derivatives.

1- (Lixofuranosyl) -2,5,6-trichloro-benzimidazole, 1- (Lixofuranosyl) -2-bromo-5,6-dichloro-benzimidazole, 1- (Lixofuranosyl) -2-methylamino- 5,6-dichloro-benzimidazole, 1- (lixofuranosyl) -2-isopropylamino-5,6-dichloro-benzimidazole, 1- (lixofuranosyl) -2-cyclopropylamino-5,6-dichloro-
Benzimidazole, 1- (Lixofuranosyl) -2-thio-5,6-dichloro-benzimidazole, 1- (Lixofuranosyl) -2-benzylthio-5,6-dichloro-benzimidazole, and 1- (Lixofuranosyl) -2- Methylthio-5,6-dichloro-benzimidazole.

As used herein, the term “pharmaceutically acceptable salt or prodrug derivative” refers to any pharmaceutically acceptable salt, ester, ether, salt of an ester, solvate such as ethanolate, or a patient. And other derivatives of the compounds of the present invention which can provide (directly or indirectly) a compound of the present invention or an active metabolite or residue thereof when administered to the subject. Particularly preferred derivatives and prodrugs increase the bioavailability of the compounds of the present invention when such compounds are administered to a mammal (eg, by making the orally administered compound more readily absorbed into the blood). Or facilitates delivery of the parent compound to a biological compartment (eg, brain or lymphatic system).

The salts of the compounds of the present invention can be derived from inorganic or organic acids and bases. Examples of acids include hydrochloric, hydrobromic, sulfuric, nitric, perchloric, fumaric, maleic, phosphoric, glycolic, lactic, salicylic, succinic, toluene-p-sulfonic, tartaric, acetic acid , Citric acid, methanesulfonic acid, ethanesulfonic acid, formic acid, benzoic acid, malonic acid, naphthalene-2-sulfonic acid, and benzenesulfonic acid. Other acids, such as oxalic acid, which are not themselves pharmaceutically acceptable, can be used in the preparation of salts of the compounds of the present invention and their intermediates in obtaining pharmaceutically acceptable acid addition salts. . Examples of bases include alkali metal (e.g., sodium) hydroxides, alkaline earth metal (e.g., magnesium) hydroxides, ammonia, and wherein _NW ^{4 +} (wherein, W is is _{C 1-4} alkyl )).

Examples of salts include acetate, adipate, alginate, aspartate,
Benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, Flucoheptanoate, glycerophosphate, hemisulfate, hebutanoate, hexanoate,
Hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate,
Lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, palmoate, pectinate, persulfate, phenylpropionate, picrate, pivalate, propionate Salts, succinates, tartrate, thiocyanate, tosylate and undecanoate. Another example of a salt is a mixture of the anion of a compound of the present invention with a suitable cation such as Na ⁺ , NH ₄ ⁺ and NW ₄ ⁺ , wherein W is C _1-4 alkyl. No.

For therapeutic use, salts of the compounds of the present invention will be pharmaceutically acceptable. However,
Salts of acids and bases that are non-pharmaceutically acceptable can also be used, for example, in the preparation or purification of a pharmaceutically acceptable compound.

The esters of the compounds of the present invention include 2′-, 3′- and / or 5′-hydr
Carboxylic acid ester obtained by esterification of a roxy group (that is, -O-
C (= O) R) wherein R is (1) a linear or branched alkyl (eg, n-
Propyl, t-butyl, or n-butyl), alkoxyalkyl (e.g.,
Xymethyl), aralkyl (eg, benzyl), aryloxyalkyl (
For example, phenoxymethyl), aryl (eg, optionally halogen, C _1-4 Alkyl or C_1-4Phenyl substituted by alkoxy or amino
(2) sulfonic acid esters such as alkylsulfonyl (eg, methanesulfonate)
Fonyl) or aralkylsulfonyl; (3) amino acid esters (eg, L-
(4) phosphonate esters; and (5) mono-, di- or triphosphate esters). Phosphate esthetic
For example, C_1-20By an alcohol or reactive derivative thereof, or by 2,3-di- (C_6-24) It can be further esterified by acyl glycerol. For such esters, unless otherwise noted, any
Alkyl residues also have 1-18 carbon atoms, specifically 1-6 carbon atoms, more specifically
Specifically, it preferably contains 1 to 4 carbon atoms. Present in such esters
Preferably, any cycloalkyl residue contains from 3 to 6 carbon atoms. This
Any aryl residue present in such esters may comprise a phenyl group.
preferable. Examples of the lixofuranosyl prodrug derivative of the present invention include, for example,
Having chemically protected hydroxyl groups (eg, O-acetyl groups), eg
For example, 2'-O-acetyl-lixofuranosyl, 3'-O-acetyl-lixofuranos
Sil, 5'-O-acetyl-lyxofuranosyl, 2 ', 3'-di-O-acetyl-li
Xofuranosyl, and 2 ', 3', 5'-tri-O-acetyl-lyxofuranosyl.

Esters of the compounds of the present invention include methyl, ethyl, propyl, butyl, isobutyl, and sec-butyl ether.

B. Use of the Antiviral Compounds of the Present Invention One aspect of the present invention provides for the in vitro, ex vivo, ex vivo, contacting of a virus with an effective amount of a compound effective to inhibit viral replication and / or growth.
The present invention relates to a method for inhibiting the replication and / or growth of a virus in vivo or in vivo. When the contacting is performed in vitro, the compound is used for screening for other antiviral compounds that can be used independently or in combination with the compounds disclosed herein. These compounds are also used to treat and / or prevent a viral infection by administering to an infected host a therapeutically effective amount of a Lixofuranosylbenzimidazole Compound of the invention. In one embodiment, such methods include administering to an infected host a composition of a pharmaceutically acceptable carrier and a therapeutically effective amount of an antiviral positive lyxofuranosylbenzimidazole compound of the invention. Can be

The term “therapeutically effective amount” is intended to encompass a prophylactically effective amount and is effective as a monotherapy or in combination with other agents to treat or prevent a viral infection in a patient. Represents an appropriate amount. As used herein, the term "treatment" refers to the alleviation of the symptoms of a particular disease in a patient, or a decrease in the virus titer in a host of ascertainable measurements or a host associated with a particular disease. According to one of the techniques in the art, it is possible to determine when a host has been "treated" by observing a reduction in viral load or relief of symptoms associated with a viral infection.
The term "prophylactically effective amount" refers to an amount effective to prevent viral infection in a host. The term "host" as used herein refers to mammals, e.g., mice,
Represents a bovine, rat or human patient.

The term “biologically acceptable carrier” is a carrier or adjuvant that can be administered to a host or patient together with a compound of the invention,
Represents those that do not destroy the pharmacological activity of the compounds of the present invention and are not toxic when administered at a dose sufficient to deliver an effective amount of the antiviral compound. Examples of suitable carriers include sterile or liquid phase carriers, such as aqueous solutions, as well as the following.

As shown below, the compounds of the present invention are potent antivirals and are particularly effective against DNA viruses, eg, herpes viruses such as HCMV, HBV and HSV-1, and are associated with carriers. Together, it's just in vitro,
Compositions for inhibiting virus regeneration and growth ex vivo or in vivo are provided. However, it is to be understood that other viruses such as HHV-6 and HIV can be inhibited by the compounds of the present invention, although not explicitly indicated. The method of measuring potency against these viruses is described below. Further, R
NA viruses can also be inhibited by the compounds of the present invention.

The compounds of the present invention can also be used in combination with other therapeutic agents to inhibit the replication or proliferation of the above-mentioned viruses and related diseases. A combination therapy according to the invention comprises administering at least one compound of the invention and at least one other pharmaceutically active ingredient. The active ingredient (s) and pharmaceutically active agents can be administered simultaneously in the same or different pharmaceutical formulations or sequentially in any order.
The amounts of active ingredient (s) and pharmaceutically active agent (s) and the relative timing of administration are selected to achieve the desired combined therapeutic effect. Preferably, the combination treatment comprises one compound according to the invention and one administration of the following agents. The term "operative combination" refers to a compound of the present invention and another compound of the present invention or another compound other than the present invention (e.g., as long as the combination does not reduce the antiviral activity of the compound of the present invention). , Ganciclovir, AZT, and foscarnet).

Examples of other active ingredients include drugs effective for treating viral infections or related diseases
Agent (1-α, 2-α, 3-α) -9- [2,3-bis (hydroxymethyl) cyclo
Robutyl] guanine [(-) BHCG, SQ-34514], oxetanosine-
G (3,4-bis (hydroxymethyl) -2-oxetanosyl] guanine), non-
Cyclic nucleosides (eg, acyclovir, valacyclovir, famciclovir)
Beer, ganciclovir, pencyclovir), acyclic nucleoside phosphone
(E.g., (S) -1- (3-hydroxy-2-phosphonylmethoxypropyl)
G) cytosine (HPMPC), a ribonucleotide reductase inhibitor such as 2
-Acetylpyridine 5-[(2-chloroanilino) thiocarbonyl] thiocarbo
Nohydrazone, 3'-azido-3'-deoxythymidine, other 2 ', 3'-dide
Oxynucleosides such as 2 ', 3'-dideoxycytidine, 2', 3'-di
Deoxyadenosine, 2 ', 3'-dideoxyinosine, 2', 3'-dideoxy
Cythymidine, a protease inhibitor such as ritonovir, indinavir, 1
41W94, Nelfina Beer, Sankina Beer, and 3S- [3R^*(1S ^* , 2R^*)]-[3-[[4-aminophenyl) sulfonyl] (2-methyl
Ropyl) -amino] -2-hydroxy-1-phenylmethyl) propyl] carba
Minic acid, tetrahydro-3-furanyl ester (141W94), oxathiola
Nucleoside analogs, such as (-)-cis-1- (2-hydroxymethyl)-
1,3-oxathiolan-5-yl) -cytosine (lamivudine) or cis-
1- (2- (hydroxymethyl) -1,3-oxathiolan-5-yl) -5
Fluorocytosine (FTC), 3'-deoxy-3'-fluorothymidine, 5-
Chloro-2 ', 3'-dideoxy-3'-fluorouridine, (-)-cis-4
-[2-amino-6- (cyclopropylamino) -9H-purin-9-yl]-
2-cyclopentene-1-methanol, ribavirin, 9- [4-hydroxy-2
-(Hydroxymethyl) but-1-yl] -guanine (H2G), tat inhibitor
For example, 7-chloro-5- (2-pyryl) -3H-1,4-benzodiazepine-
2- (H) -one (Ro5-3335), 7-chloro-1,3-dihydro-5-
(1H-pyrrol-2-yl) -3H-1,4-benzodiazepin-2-amine
(Ro24-7429), interferons such as (α-interferon,
Renal excretion inhibitors such as probenecid, nucleoside transport inhibitors such as dipyrida
Mohr, pentoxifylline, N-acetylcysteine (NAC), procysteine
, (Α-trichosanthin, phosphonoformic acid, and immunomodulators such as
-Leukin II or thymosin, granulocyte-macrophage colony stimulating factor,
Tropoetin, soluble CD₄And its genetically engineered derivatives, or non-nucleosides
Reverse transcriptase inhibitors such as nevirapine (BI-RG-587), loviride (α
-APA) and delabridine (BHAP), and phosphonoformic acid
.

The compounds of the present invention may comprise the antiviral agents zidovudine (AZT) and / or 3TC
Could also be used to treat HCMV and HSV-1 infections in AIDS patients who have already been administered. In combination therapy with AZT, ganciclovir A
There is an advantage that toxicity is small as compared with the combination with ZT. The compound of the present invention is represented by A
Combination with ZT may result in less cytotoxicity in cultured human cells than either agent alone (ie, antagonism). In contrast, the combination of ganciclovir and AZT may be more cytotoxic in human cells than using either of these agents alone.

The present invention relates to a method of contacting a cell or an individual of a cell infected with a virus with an effective amount of a compound of the present invention under suitable conditions so that virus regeneration and proliferation is inhibited. Also provided is a method of reducing or inhibiting the reproduction and growth of a virus in E. coli. One of the techniques in the art facilitates when virus regeneration and proliferation is reduced or inhibited by observing a decrease in virus titer or increased viability of infected cells compared to untreated infected cells. Can be determined. Methods for analyzing virus titers are well known to those skilled in the art and are exemplified below. It is readily understood that by inhibiting and reducing viral replication and growth, viral infectivity is also inhibited and diminished, and cells are appropriately treated for viral infection. Associated etiologies are also treated. In one aspect, a herpes virus such as HCMV, a hepatitis virus, eg, hepatitis B virus (HBV), or an HSV-1 infection is treated or prevented.

For the purposes of the present invention, “cells” include, but are not limited to, mammalian cells such as mouse cells, bovine cells, rat cells, woodchuck cells, monkey cells or human cells. Not done. Viruses that are effectively treated by the compounds, compositions and methods of the present invention include DNA and RNA viruses, especially herpes viruses. Examples of herpes virus or herpes virus include herpes simplex virus type 1 (HSV-1), herpes simplex virus type 2 (H
SV-2), varicella-zoster virus (VZV), Epstein-Barr virus (EB
V), human cytomegalovirus (HCMV), human herpesvirus 6 (H
HV-6), human herpesvirus 7 (HHV-7), and human herpesvirus 8 (HHV-8). The compounds of the present invention include HCMV and HSV-
1 and is particularly useful in the treatment of related etiologies such as restenosis. They can preferably be used for the treatment of hepatitis-related diseases such as hepatocellular carcinoma (US Pat.
679, 342).

[0066] Effective amounts are readily determined by one skilled in the art, and will vary with the cell, virus, and therapeutic purpose being treated. For example, when using drugs in cell culture, it is important that the amount of drug not be cytotoxic to the cells.

“Suitable conditions” include in vitro, ex vivo or in vivo. When the method is performed in vitro, contacting can be performed by incubating the cells with an effective antiviral amount of a compound effective to inhibit regeneration and growth of the cells or cell cultures. The compound can be added directly to the medium or can be combined with the carrier before adding to the cells. In vitro, this method is particularly useful for virus regeneration, propagation, and thus inhibition of infection in test cell cultures. Ex vivo, the compounds are useful for inhibiting virus regeneration and growth before blood and plasma are reintroduced into the patient.

The use of compounds and methods in vitro also provides powerful bioassays for screening new agents or compounds that provide similar or increased antiviral activity. Using the methods described below, the agent being tested is analyzed under the same conditions as the compound of the invention. The antiviral and cytotoxicity of the test agent can then be compared to the compounds of the present invention.

These compounds are shown below to be particularly effective against HCMV and HSV-1, but by using the methods described herein and other methods well known to those skilled in the art, It is within the scope of the present invention to effectively treat a virus of the invention with a compound of the present invention. Other viruses that can be treated in a manner as defined herein and within the scope of the present invention include all viruses of the family Herpes, and human immunodeficiency virus (HIV) and hepatitis viruses such as B Hepatitis virus (HBV). Methods for determining the efficacy of any of the compounds of the present invention on HBV are well known in the art and are described, for example, in US Pat. No. 5,399 to Daluge.
No., 580, 580.

[0070] Another virus of the hepatitis virus family that can be treated in the manner defined in the present invention is the hepatitis C virus (HCV). U.S. Pat. No. 5,679,342 issued to Houghton et al. Describes in detail a method of using an extracellular cell line infected with HCV to screen for compounds that are highly active against HCV. Has been described. Briefly, the method comprises: (a) providing a composition comprising a compound of the present invention to be tested; (b) providing an extracorporeal cell line capable of infecting HCV; Providing a biological sample comprising HCV, wherein (d) (a) and (d)
The composition of c) is incubated with the cell line of (b) under conditions capable of infecting HCV in the cell line in the absence of (a), and (e) inhibiting the inhibition of viral infection after the incubation. It is characterized by detecting. U.S. Pat. No. 5,679,
Preferred cell lines disclosed in US Pat. No. 342 include hepatocytes, macrophages, more preferably Kupffer macrophages, and B lymphocytes. Cell lines derived from hepatocellular trachea are also suitable for use in the assays described above. (a) and (b) under conditions capable of replicating HCV in a cell line in the absence of (a)
The above assay can also be used to test inhibition of viral replication by incubating the composition of step) and then detecting inhibition of viral replication after incubation.

Another method known in the art for testing the antiviral activity of compounds against HCV is described, for example, in Lain et al., (1991) Nucleic Acids Res. 69: 172.
0-1726 and Kim et al., (1995) Biochem. Biophys. Res. Comm. 160-166.

When the method is performed in vivo on a subject, such as a human patient, the compound is added to a pharmaceutically acceptable carrier and the subject, such as a human patient or a mouse, rat, woodchuck or monkey, is prepared. Can be administered systemically or locally to any mammal.

The composition can also be administered to a subject or individual susceptible or at risk for a viral infection, such as HCMV, HSV-1 or herpes virus infection. Accordingly, the present invention provides a method of administering a prophylactically effective amount of a compound or composition to a subject under appropriate conditions to inhibit viral replication, growth or infection, thereby effecting viral replication, growth and / or viral infection in the subject. Also provided is a prophylactic method of inhibiting. A “prophylactically effective amount” is an amount that inhibits viral infection, regeneration, and growth in a subject that has been immunized with a virus that is nontoxic to the cells being treated and the subject.

By preventing or inhibiting the growth, infection and replication of the virus in a subject or individual, the compositions and methods of the invention provide for inclusion body disease, blindness, mononucleosis, restenosis (HCMV), varicella Shingles (varicella-zoster virus); infectious mononucleosis, glandular, fever, and Burkitt's lymphoma (Epstein-Barr virus); herpes simplex (herpes simplex type 1); genital herpes (simple) Herpes virus 2); childhood varicella (human herpes virus 6; human herpes virus 7)
(Type); treatment, prevention or amelioration of symptoms and diseases associated with viral infections such as Kaposi's sarcoma (human herpesvirus 8). Accordingly, the invention relates to viral infections such as HCMV, HSV-1 and herpes virus infections such as restenosis, opportunistic infections (eg, retinal infections, gastrointestinal infections, pneumonia, CNS,
Infection or liver injury) and intrauterine infection, by administering to a subject an effective amount of a compound of the present invention under suitable conditions, ameliorating the disease or condition,
Also provided are methods of improvement, prevention or treatment by preventing or treating.

Restenosis is a stenosis of a blood vessel that can be caused by damage to the vessel wall, for example, damage caused by balloon angioplasty or other surgical procedures, and a hyperproliferation of smooth muscle in the wall of the treated vessel. It is characterized by. Post-angioplasty restenosis (RFA) is seen in patients who have been treated for coronary artery disease by balloon angioplasty. In many RFA patients, viral infections of the patients, especially by CMV and / or HHV-6, appear to play an important role in the proliferation of treated coronary artery smooth muscle cells.

Restenosis can occur after many surgical procedures, such as transplant surgery, vein transplantation, coronary bypass grafting, and most often after angioplasty.

Angiogenesis is a constriction of the peripheral, renal and coronary vasculature due to atherosclerosis, which typically compresses blood vessel walls with a pressurized balloon catheter and / or
Or a surgical procedure that removes by tearing. Unfortunately, cases,
In 25-50% of cases, especially those involving the coronary vasculature, alternatives to balloon catheters, such as pulsed lasers and rotary cutters, require restenosis after angioplasty, as the treated vessels undergo restenosis within months. It has been developed to reduce or prevent but has not been very successful. Numerous drugs, including anticoagulants and vasodilators, have been tried, but the results have been disappointing or inconclusive.

[0078] There is a strong body of evidence from studies conducted in vitro and in vivo therapy that restenosis is a multifactorial process. Several cytokines and growth factors act synergistically to stimulate the migration and proliferation of vascular smooth muscle cells (SMCs) and the production of extracellular matrix material that accumulates and blocks blood vessels. In addition, growth inhibitors act to inhibit SMC proliferation and production of extracellular matrix material. Accordingly, the compounds of the present invention can be used in methods for preventing or treating restenosis in a subject or patient that is susceptible.

In vivo administration can be as a single dose during the course of treatment, continuous or intermittent. Methods for determining the most effective means and dosage of administration are well known to those of skill in the art and will vary with the composition used for treatment, the target virus, the purpose of the treatment, the target cell being treated, and the subject being treated. Single or multiple doses can be administered, the dose level and pattern being selected by the treating physician. Suitable dosage formulations and methods of administering the compounds can be found below.

All of the compounds of the present invention are HCMV, herpes virus infection and HSV-1
, And is cytotoxic in most cases. It will be appreciated that compounds of the present invention that have relatively high antiviral activity / cytotoxicity, ie, exhibit good selectivity, are preferred. Antiviral therapy according to the present invention may be used to treat viral infections and in certain situations, for example, in patients with reduced immunity, such as bone marrow or organ transplant patients and HIV patients who are particularly susceptible to HCMV, herpes virus or HSV-1 infection. Includes prophylactic treatment that may be desired.

The compounds and compositions of the present invention can be used in the manufacture of medicaments, and for antiviral treatment of humans and other animals by conventional procedures, eg, by administering the active ingredient in a pharmaceutical composition.

The pharmaceutical compositions can be administered topically, orally, nasally, parenterally or by inhalation therapy and can be in the form of tablets, lozenges, granules, capsules, pills, ampules, suppositories or aerosols. Can be taken. They can also take the form of ointments, gels, pastes, creams, sprays, lotions, suspensions, solutions and emulsions, syrups, granules or powders with the active ingredient in an aqueous or non-aqueous diluent. In addition to a compound of the present invention, the pharmaceutical compositions may also contain other pharmaceutically active compounds or more than one compound of the present invention.

More specifically, compounds of the formulas of the present invention, also referred to herein as active ingredients, may be orally, rectally, nasally, topically (such as transdermal, aerosol, buccal and sublingual), vaginal, non- It can be administered for therapeutic purposes by any suitable route, such as oral (such as subcutaneous, intramuscular, intravenous and intradermal), and pulmonary. It will also be appreciated that the preferred route will vary depending on the condition and age of the patient, the virus being treated, and the nature of the infection.

In general, suitable dosages for each of the above viral infections, eg, HCMV and HSV-1, range from about 0.1 to about 250 mg / kg patient weight / day;
Preferably it is in the range of about 1 to about 100 mg / kg body weight / day, most preferably in the range of about 5 to about 20 mg / kg body weight / day. Unless otherwise stated, all active ingredient weights are calculated as parent compounds of the formulas of the invention relative to the salt or ester,
Weight increases proportionately. The desired dose is administered at appropriate intervals during the day.
It is preferably provided as small doses of 3, 4, 5, 6 or more. These small doses may be administered, for example, in unit dosage forms containing from about 10 to about 1000 mg, preferably from about 20 to about 500 mg, most preferably from about 100 to about 400 mg active ingredient / unit dosage form. It will be appreciated that appropriate doses of the compounds and compositions of the present invention may vary with the type and severity of the viral infection and may vary from patient to patient. Determining the optimal dose will usually involve considering the level of therapeutic effect on any dangerous or adverse side effects of the antiviral treatment of the present invention.

Ideally, the active ingredient will have a peak plasma concentration of the active compound from about 2 μM to about 100 μM.
It should be administered at μM, preferably from about 5 μM to about 70 μM, most preferably from about 1 to about 50 μM. This may include, for example, intravenous injection of an about 0.1 to about 5% solution of the active ingredient, optionally in saline, or, for example, about 0.1 to about 0.1% of the active ingredient.
It is achieved by oral administration as a tablet, capsule, or syrup containing up to about 250 mg / kg. Desirable blood concentrations are provided by continuous infusion to provide about 0.01 to about 5.0 mg / kg / hour, or by providing about 0.4 to about 15 mg / kg of active ingredient.
It can be maintained by intermittent infusions. The use of a combination procedure is intended to provide a combination therapy in which the total dose of each component antiviral drug is less than would be required when using each therapeutic compound or agent alone.

While the active ingredient can be administered alone, a medicament comprising at least one active ingredient as defined above together with one or more pharmaceutically acceptable carriers and optionally other therapeutic agents. It is preferably provided as a formulation. Each carrier must be "acceptable" in the sense that it is compatible with the other ingredients of the formulation and will not be discreet for the patient.

Formulations suitable for oral, rectal, nasal, topical (such as transdermal, buccal and sublingual), vaginal, parenteral (such as subcutaneous, intramuscular, intravenous and intradermal) and pulmonary administration Are included. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well-known in the art of pharmacy. Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients.
In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.

Formulations of the present invention suitable for oral administration include powders or granules, as discrete units, each containing a predetermined amount of the active ingredient, such as capsules, cachets or tablets.
It can be provided as a solution or suspension in an aqueous or non-aqueous liquid, or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be presented as a bolus, electuary or paste.

A tablet may be made by compression or moulding, optionally with one or more accessory ingredients. Compressed tablets are active ingredients in free flowing form, such as powder or granules, in suitable equipment, optionally with binders (eg, povidone, gelatin, hydroxypropylmethylcellulose), lubricants, inert diluents, It can be prepared by compressing a mixture with a preservative, disintegrant (e.g., sodium starch glycolate, cross-linked povidone, cross-linked sodium carboxymethyl cellulose), a surfactant or dispersant. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide slow release or active ingredient release, for example using hydroxypropylmethylcellulose in various ratios, to provide the desired release curve. Controlled release can be provided. Tablets may optionally be provided with an enteric coating, to provide release in parts of the gut other than the stomach.

Formulations suitable for topical administration in the mouth include lozenges which comprise the active ingredient, usually in a flavored basis of sucrose and acacia or tragacanth, gelatin and glycerin or sucrose and acacia. Pastes, which comprise the active ingredient in an inert principal component, such as, and mouthwashes which comprise the active ingredient in a suitable liquid carrier.

Pharmaceutical compositions for topical administration according to the present invention can be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oily products. Alternatively, the formulation may comprise a patch or bandage, such as a bandage or adhesive plaster impregnated with the active ingredient and optionally one or more excipients or diluents.

For infections of the eye or other external tissues, for example mouth and skin, the formulation may be
For example, about 0.075 to about 20% (weight / weight), preferably about 0.2 to about 25%
It is preferably administered as a topical ointment or cream containing the active ingredient in an amount of (w / w), most preferably from about 0.5 to about 10% (w / w). When formulated in an ointment, the active ingredients may be employed with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredients may be formulated in a cream with an oil-in-water cream base.

If desired, the aqueous phase of the cream base may contain at least about 30% of a polyhydric alcohol, ie, two alcohols such as propylene glycol, butane-1,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol. Alcohols having the above hydroxyl groups, and mixtures thereof can be included. Topical formulations may preferably include a compound that enhances absorption or penetration of the active ingredient from the skin or other affected areas. Examples of such transdermal penetration enhancers include dimethyl sulfoxide and related analogs.

The oil phase of the emulsion of the present invention may be composed of known components in a known manner. This phase may comprise only emulsifiers (also known as emulgents), but comprises at least one emulsifier and a fat or oily product or a mixture of a fat and an oily product. Is desirable. The hydrophilic emulsifier is preferably formulated together with a lipophilic emulsifier acting as a stabilizer. It is also preferred to incorporate both the oily product and the fat. The emulsifier (s)
With or without stabilizers) make up so-called emulsifiable waxes, which, together with the oily products and / or fats, make up the so-called emulsifiable ointment base which forms the oily dispersed phase of the cream formulation.

[0095] Suitable emulsions and emulsion stabilizers for use in the formulations of the present invention include Tween 60, Span 80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate, and sodium lauryl sulfate.

The choice of an oily product or fat suitable for the formulation depends on the very low solubility of the active ingredient in most oily products suitable for use in pharmaceutical emulsion formulations.
It is based on achieving the desired cosmetic properties. Accordingly, the cream is preferably a washable product which is non-greasy, non-staining and suitable in consistency to prevent leakage from tubes and other containers. Linear or branched mono- or dibasic alkyl esters such as di-isoadipate, isocetyl stearate,
Propylene glycol diester of coconut oil fatty acid, isopropyl myristate,
A mixture of decyl oleate, isopropyl valmitate, butyl stearate, 2-ethylhexyl balmitate, or a branched ester known as Crodamol CAP can be used, with the last three being the preferred esters. These can be used alone or in combination depending on the properties required. Alternatively, high melting point lipids such as white petrolatum and / or liquid paraffin can be used.

Formulations suitable for topical administration to the eye include eye drops wherein the active ingredients are dissolved or suspended in suitable carrier, especially an aqueous solvent for the active ingredients. The active ingredient may be present in such formulations in an amount of about 0.5% to about 20%, preferably about 0.5% to about 10%, especially about 1%.
. It is preferably present at a concentration of 5% (weight / weight).

[0098] Formulations for rectal administration may be presented as a suppository with a suitable base comprising, for example, cocoa butter or a salicylate.

Formulations suitable for vaginal administration are provided as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing, in addition to the active ingredient, carriers known in the art to be suitable can do.

Formulations suitable for nasal administration, wherein the carrier is solid, include a coarse powder having a particle size of, for example, about 20 to about 500 microns, which is obtained by inhalation, ie, It is administered by rapid inhalation through a nasal passage from a container of the powder fixed near the nose. Formulations suitable for administration as a nasal spray, nasal drop or the like, where the carrier is a liquid, or by aerosol administration with a nebulizer, include aqueous or oily solutions of the active ingredient.

Formulations suitable for parenteral administration include aqueous or non-aqueous solutions which may include antioxidants, buffers, bacteriostats and solutes which make the formulation isotonic with the blood of the intended patient. Aqueous and isotonic sterile injectable solutions, and suspensions and thickening agents as well as aqueous and liposomes, or other particulate systems in which the compound is designed to target blood components or one or more organs Non-aqueous sterile suspensions are included. The formulations can be presented in single or multi-dose sealed containers, such as ampules and vials, and require only the addition of a sterile liquid carrier, such as water for injection, immediately before use. Can be stored under conditions. Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules and tablets of the kind previously described.

Preferred unit dosage formulations are those containing a daily dose or unit, daily sub-dose, as herein above recited, or an appropriate fraction thereof, of the active ingredient.

The formulations of the present invention can contain, in addition to the components specifically mentioned above, other agents commonly known in the art for the type of formulation desired, for example, those suitable for oral administration And additional agents such as sweeteners, thickeners and flavoring agents.

The compounds of the formula of the invention may also be provided for use in the form of a veterinary formulation, which may be prepared, for example, by methods conventional in the art.

C. Production method of antiviral compound of the present invention 2,3,5-tri-O-acetyl-glycofuranosyl nucleoside is 1,2
, 3,5-tetra-O-acetyl-glycoside can be prepared by a modified Vorbrueggen method (Vorbrueggen, H., Krolikiewicz, K., Bennua, B. "Using trimethylsilyl triflate and perchlorate as catalysts" Nucleoside synthesis
(Nucleoside Synthesis with Trimethylsilyl Triflate and Perchlorate as Ca
talyst) "Chem. Ber. 1981, 114: 1234-55). Anomer arrangement is
In most cases it is predominantly trans with respect to the 1'-heterocyclic residue and the 2'-O-acetyl group (Baker, BR, Joseph, JP, Schaub, RE, Williams, JH
"Synthetic studies on puromycin. V. 6-Dimethylamino-9- (2'-acetylamino-β-D-glucoviranosyl) purine (Puromycin Synthetic Studies.
V. 6-Dimethylamino-9- (2'-acetylamino-β-D-glucopyranosyl) purine) "J. Or
g. Chem. 1954, 19, 1786-1792). For this method, tetra-
O-acetyl-D-lyxofuranose (compound 2b) and tetra-O-acetyl-L-lyxofuranose (compound 2a) were prepared for use as glycosyl donors in similar homestays.

Starting from commercially available D-xylose, tetra-O-acetyl-D-xylofuranose (compound 2b) was prepared in three steps using the method developed by Guthrie and Smith (Koszalka, GH, Chamberlain, SD, Daluge, SM, Boyd, FL,
Tidwell, JH, Martin, MT, Harvey, RJ Frick, LW, Perkins, DG, W
ang, LH, Drach, JC, Townsend, LB, Biron, KK Benzimidazoles for the treatm for the treatment of human cytomegalovirus infection
ent of human cytomegalovirus infection) / The 2nd International Conference: Nucleosides,
Nucleotides and their biological applications (In XII International Roundtable
Nucleosides, Nucleotides and their Biological Applications), La Jolla, California, September 1996). Following the reported synthesis, a 3: 1 mixture of each isomer of furanose and pyranose was obtained as determined by ¹ H NMR. To further optimize the conditions for the furanose isomer, Dowex-50 acidic ion exchange resin and acetyl chloride were used in place of sulfuric acid in the first step of the process. 3-step method instead of these new ^conditions, as measured by 1 H NMR, furanose / pyranose ratio 1.5: 1 (Do
wex) and 5: 1 (acetyl chloride). Since the pyranose isomers are formed in each case, sulfuric acid or acetyl chloride conditions proved to be sufficient,
After silica gel chromatography, compound 2b was converted to a mixture of anomers at about 50%
In the total yield of

Using a method similar to that used for the preparation of TCRB (Townsend, LB, Devivar,
RV, Turk, ST, Nassiri, MR, Drach, JC Design, synthesis and antiviral activity of certain 2,5,6-trihalo-1- (β-D-ribofuranosyl) benzimidazoles and Antiviral Activity of Certain 2,
5,6-Trihalo-1- (β-D-ribofuranosyl) benzimidazoles) J. Med.Chem. 1995, 38
, 4098-4105, and Kawashima, E., Gupta, PK, Devivar, RV, Townsend,
LB 2,5,6-Trichlorobenzimidazo
le) / Nucleic Acid Chemistry; part 4, Townsend, LB, T
ipson, RS supervision; John Wiley and Sons, New York, 1991, 24-2
6), 2,5,6-trichloro-benzimidazole (TCB, compound 1
, Kawashima, E., Gupta, PK, Devivar, RV, Townsend, LB 2,5,6-
Trichlorobenzimidazole (2,5,6-Trichlorobenzimidazole) / Nucleic acid chemistry; Part 4 (Nucleic Acid Chemistry; part 4), supervised by Townsend, LB, Tipson, RS;
John Wiley and Sons, New York, 1991, pp. 24-26), and bis (trimethylsilyl) acetamide (BSA, Vorbrugg) in dry acetonitrile.
en, H., Hofle, G. On the Mechanism of Nucleoside Synthesis
leoside Synthesis) (see Chem. Ber. 1981, 114, 1256-1268) followed by trimethylsilyl trifluoromethanesulfonate (TMSOTf).
Is glycosylated with compound 2b in the presence of compound 3b 1- (2 ′, 3 ′, 5 ′
-Tri-O-acetyl-α-D-lyxofuranosyl) -2,5,6-trichlorobenzimidazole was obtained. Compound 3b 1- (2 ′, 3 ′, 5′-tri-O—
Acetyl-α-L-lyxofuranosyl) -2,5,6-trichlorobenzimidazole was prepared in a similar manner.

[0108]

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The compound 3b is deprotected under basic conditions to give 1- (α-D-lyxofuranosyl)
-2,5,6-Trichlorobenzimidazole (compound 4b) was obtained. Similarly, by deprotecting compound 3a, 1- (α-L-lyxofuranosyl) -2,5,6
-Trichlorobenzimidazole (compound 4a) was obtained.

[0110]

Embedded image

As previously reported (Harrison, D., Ralph, JT. Nucleophilic substitution of 2-chlorobenzimidazole. Part 1. Benzimidazolin-2-one and 2
-Formation of alkoxybenzimidazole (Nucleophilic Substitution Reaction)
of 2-Chlorobenzimidazoles. Part I. Formation of Benzimidazolin-2-ones an
d 2-Alkoxybenzimidazoles) J. Chem. Soc. 1965, 236-239), the 2-chloro substituent of 1-substituted 2,5,6-trichlorobenzimidazole can be conveniently modified by various nucleophilic groups. Can be replaced by After this method, compound 3
b was treated with anhydrous hydrogen bromide using dichloromethane and then deprotected under basic conditions to give 2-bromo-5,6-dichloro-1- (α-D-lyxofuranosyl) benzimidazole (compound 5b). Obtained. Compound 3a was treated in the same manner to give 2-bromo-
5,6-Dichloro-1- (α-L-lyxofuranosyl) benzimidazole (compound 5a) was obtained.

[0112]

Embedded image

Further, 1- (α-D-lyxofuranosyl) -2-methylamino-5,6-dichloro-benzimidazole (compound 6b), which is a methylamino derivative, was treated with 33% methylamine in a sealed container. / 1 by treating with ethanol
Prepared in stages. Compound 6a, 1- (α-L-lyxofuranosyl) -2-methylamino-5,6-dichloro-benzimidazole, was prepared in a similar manner to Compound 3
Prepared from a.

[0114]

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The isopropylamino derivative 1- (α-D-lyxofuranosyl) -2-isopropylamino-5,6-dichloro-benzimidazole (compound 7b) and the cyclopropylamino derivative 1- (α-D-lyxofuranosyl) ) -2-
Cyclopropylamino-5,6-dichloro-benzimidazole (compound 8b)
Was conveniently prepared by treating the deprotected nucleoside, compound 4b, with the appropriate primary amine in ethanol. In a similar manner, 1- (α-L
-Lixofuranosyl) -2-isopropylamino-5,6-dichloro-benzimidazole (compound 7a) and 1- (α-L-lyxofuranosyl) -2-cyclopropylamino-5,6-dichloro-benzimidazole (compound 8a) Is
Prepared from compound 4a.

[0116]

Embedded image

Further, the 2-thio derivative 1- (α-D-lyxofuranosyl) -2-thio-
5,6-Dichloro-benzimidazole (compound 9b) was prepared by heating compound 4b in an ethanol / thiourea mixture at reflux for 19 hours.
Compound 9a, 1- (α-L-lyxofuranosyl) -2-thio-5,6-dichloro-benzimidazole, was prepared in a similar manner.

[0118]

Embedded image

Compound 9b is also commercially available 5,6-dichlorobenzimidazole-2-thione (Compound 10, Devivar, RV, Kawashima, E., Revankar, GR, Breitenbach, JM
., Kreske, ED, Drach, JC, Townsend, LB Benzimidazole ribonucleosides: certain 2- (alkylthio)-and 2- (benzylthio) -5,6
-Dichloro-β-D-ribofuranosyl) benzimidazole design, synthesis and antiviral activity (Ribonucleosides: Design, Synthesis, and antiviral Act)
ivity of Certain 2- (Alkylthio)-and 2- (Benzylthio) -5,6-dichloro-β-D-rib
ofuranosyl) benzimidazoles) J. Med. Chem. 1994, 37, 2942-2948), which is silylated with BSA in dry acetonitrile and then TMSOTf
Prepared by glycosylation with compound 2b in the presence of and after deprotection compound 9b was obtained. This result clearly shows that glycosylation occurred at N-1 and not at the 2-thio residue. Compound 9a was similarly prepared.

[0120]

Embedded image

Finally, compound 9b was treated with NH ₄ OH in acetonitrile / water and then alkylated with benzyl bromide or methyl iodide to give 2-benzylthio-5,5 respectively.
6-dichloro-1- (α-D-lyxofuranosyl) benzimidazole (compound 11b) and 5,6-dichloro-1- (α-D-lyxofuranosyl) -2- (
Methylthio) benzimidazole (Compound 12b) was obtained. In the same way,
Benzylthio-5,6-dichloro-1- (α-L-lyxofuranosyl) benzimidazole (compound 11a) and 5,6-dichloro-1- (α-L-lyxofuranosyl) -2- (methylthio) benzimidazole (compound 12a) ) Got.

[0122]

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In another method, the β-L-analog is first converted to 2,5,6-trichloro-1- (3 ′, 5′-di-O with hydrazine hydrate, pyridine and acetic acid. -Benzoyl-β-L-lyxofuranosyl) benzimidazole (Compound 13). Next, compound 13 is reacted with triflic anhydride and pyridine in dichloromethane to give 2,3′-O-cyclo-5,6-dichloro-1- (β-L-lixofuranosyl) benz. Imidazole (compound 14) was obtained. Next, compound 14 was reacted with isopropylamine in ethanol to give 2-isopropylamino-5,6-dichloro-1.
To (β-L-lyxofuranosyl) benzimidazole (Compound 15) was obtained.

[0124]

Embedded image

The anomeric configuration of each compound is determined by Baker's rule (Baker, BR, Jo
Seph, JP, Schaub, RE, Williams, JH "Synthetic studies on puromycin. V. 6-Dimethylamino-9- (2'-acetylamino-β-D-glucoviranosyl) purine Dimethylamino-9- (2'-acetyla
mino-β-D-glucopyranosyl) purine) ”, J. Org. Chem. 1954, 19, 1786-1792), confirmed by NOE experiments (Rosemeyer, H., Toth, G., Seela).
, F. "Assignment of Anomeric Configuration of D-Ribo-, NOE difference spectral analysis method. Arabino-, 2'-Deoxyri
bo-, and 2 ', 3'-Dideoxyribonucleotides by NOE Difference Spectoscopy)''Nu
cleosides, Nucleotides 1989, 8, 587-597).

Accordingly, in one aspect, the present invention relates to a process for the preparation of a D- or L-lyxofuranosylbenzimidazole compound of the invention, comprising: (a) Reacting with a compound of formula (III),

Embedded image(In the above formula, R²Is selected from the group consisting of -Cl, -Br and = S;⁹, R ^Ten Or R¹¹Are independently the same or different and are -H or
(B) then performing one or more of the following steps (i) to (viii): (i) from the product of (a) one or more hydroxyl protecting groups are present in case of
(Ii) reacting the product of (a) with HX, wherein X is selected from the group consisting of -Cl, -Br, -F and -I, and (iii) ( The product of a) is⁸NH₂(Where R⁸Is -H or 1-6
(Iv) is a linear, branched or cyclic alkyl group having three carbon atoms).₂NCSNH₂(V) The product of (a) is converted to C₆H₅CH₂X (where X is selected from the group consisting of -Cl, -Br, -F and -I), (vi) reacting the product of (b) (iv) with C₆H₅CH₂X (wherein X is -Cl, -Br,
(Vii) reacting the product of (a) with CH_Three(Viii) reacting the product of (b) (iv) with CH_ThreeReacting with I.

General Chemical Methods Melting points are measured on a Thomas-Hoover apparatus and are uncorrected. Silica gel SilicAR 40-63 microns 230-400 mesh (Mallinckrodt) was used for chromatography. Thin layer chromatography (TLC) pre-notched
Performed on SilicAR 7GF plates (Analtech, Newark, DE). The TLC plates were developed with the following solvent systems: System 1 (2% MeOH / CHCl ₃ , volume / volume), System 2 (10% MeOH / CHCl ₃ , volume / volume), System 3 (35% EtOAc).
c / hexane, volume / volume), system 4 (25% EtOAc / hexane, volume / volume), system 5 (5% MeOH / CHCl ₃ , volume / volume), system 6 (15% MeOH /
CHCl ₃ , volume / volume), system 7 (20% EtOAc / hexane, volume / volume)
And system 8 (50% EtOAc / hexane, v / v). Compounds were visualized by irradiation with ultraviolet light (254 nm) or by treatment with 10% methanolic sulfuric acid followed by carbonization on a hot plate. Evaporation was performed under reduced pressure (water-flow aspirator) at a bath temperature not exceeding 45 ° C., unless otherwise specified. ¹ H NMR spectra were recorded on a Bruker 200, 300, 360 or 500 MHz instrument. Chemical shifts are expressed in parts per million relative to the standard chemical shift of the solvent _{DMSO-d 6 (d = 2.50} ). All ¹ H NMR measurements recorded were performed by homonuclear decoupling experiments, except for compound 6a, which was determined by COSY experiments. Microanalysis experiments (summarized in Table 1) were performed at the University of Michigan, Department of Chemistry, and are within ± 0.4% of theoretical unless otherwise noted. Unless otherwise noted, all materials are
Obtained from supplier.

[0128]

【Example】

Some antiviral compounds of the present invention are described in the following examples, which are provided by way of illustration and not limitation.

Compound 3a 1- (2,3,5-tri-O-acetyl-α-L-lyxofuranosyl) -2,5
, 6-Trichlorobenzimidazole A 500 ml round bottom flask equipped with a Claisen adapter and a stirrer was evacuated and flushed with argon. Next, 2,5,6-trichlorobenzimidazole (Kawash
ima, E., Gupta, PK, Devivar, RV, Townsend, LB 2,5,6-Trichlorobenzimidazole / Nucleic acid chemistry; Part 4 (Nuc
leic Acid Chemistry; part 4), Townsend, LB, Tipson, RS supervision; John Wil
ey and Sons, New York, 1991, pp. 24-26) (Compound 1, 1 .74G, a 7.85 mmol) was suspended in dry _CH 3 CN (100 ml), bis (trimethylsilyl) acetamide (1.94 ml, (8.84 mmol) was added dropwise via syringe, during which time the heterocycle dissolved. 1,2,3,5-tetra-O-
Acetyl-L-lyxofuranose (Kam, BL, Barascut, J.-L., Imbach, J.-L
"A general method of synthesis and isolation of tetra-O-acetyl-D-aldopentofuranose and a study by NMR spectroscopy (A General Method of Synthes
is and Isolation, and an NMR-Spectroscopic Study, of Tetra-O-acetyl-D
-Aldopentofuranoses) "Carbohydrate Res. 1979, 69, see 135-142) (of compound 2a, 3.25 g, 10.2 mmol) after was added to the stirred solution which was dissolved in _CH 3 CN (50 ml) TMSOTf (1.8 ml, 9.3 mmol) was immediately added. After 20 hours, the solvent was distilled off under reduced pressure to obtain a yellow residue. This residue was dissolved in ethyl acetate (100 ml) and washed successively with water, NaHCO ₃ (sat.) And brine (1 × 75 ml each). The organic layer was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain a yellow oily product. The oily product was subjected to column chromatography (3 × 25 cm, solvent system 3) and the appropriate fractions were combined to give 2.59 g (67%) of compound 3a as a yellow glass. This glassy product was used in subsequent reactions without further purification. Rf = 0.80 (solvent system 1). ¹ H NMR (DMSO-d ₆ ): δ 8.19 (s
, 1H), 8.00 (s, 1H), 6.28 (d, 1H, J = 7.9 Hz), 5
. 97 (m, 1H), 5.74 (m, 1H), 5.17 (m, 1H), 4.26
(M, 2H), 2.19 (s, 3H), 2.03 (s, 3H), 1.96 (s,
3H). HRMS calculated for CHN: M ⁺ , 478.0010. Measured value:
478.00098 (M ⁺ ).

[0130]Compound 3b 1- (2,3,5-tri-O-acetyl-α-D-lyxofuranosyl) -2,5
, 6-trichlorobenzimidazole The procedure was as for compound 3a except that compound 2b was used instead of compound 2a.
Is the same as described above. TLC (same spot in solvent system 3) and
The roton spectrum was identical to that obtained for compound 3a. Yield: 3.
40 g (88%), yellow glassy product. HRMS calculated for CHN: M ⁺ , 478.0010. Obtained: 478.0085 (M⁺).

Compound 4a 1- (α-L-lyxofuranosyl) -2,5,6-trichlorobenzimidazole A 100 ml round bottom flask was charged with compound 3a (303 mg, 0.65 mmol), which was then added with ethanol and water. Was dissolved in 50 ml of an equimolar mixture (vol / vol). After adding anhydrous sodium carbonate (212 mg, 2.0 mmol) to the stirring solution, the reaction mixture was stirred at room temperature for another 3 hours. Acetic acid (2 ml) was added, and the solvent was distilled off under reduced pressure. The resulting solid was dissolved in ethyl acetate and the solution was washed successively with water, NaHCO ₃ (sat.) And brine (1 × 50 ml each). The organic layers were collected and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was dried under vacuum to obtain 205 mg of compound 4a as a white foam product. Rf = 0.30 (solvent system 2). Melting point: 184-185 [deg.] C. _{^{1 H NMR (DMSO-d 6}} ): δ7.
98 (s, 1H), 7.92 (s, 1H), 5.64 (d, 1H, J = 9.3H)
z), 5.49 (d, 1H, J = 3.2 Hz, D ₂ O exchangeable), 5.40 (d
, 1H, J = 3.8 Hz, D ₂ O exchangeable), 5.27 (d, 1H, J = 6.5)
Hz, D ₂ O exchangeable), 4.25 (m, 1H), 4.02 (d, 1H, J = 1)
1.6 Hz), 3.92 (m, 1H), 3.79 (d, 1H, J = 12.4 Hz)
), 3.71 (m, 1H). C ₁₂ H ₁₁ O ₄ N HR calculated for ₂ Cl ₃
MS: M ^<+> , 351.9784. Found: 351.9782 (M ⁺ ). Analysis _{(C 12 H 11 O 4 N} 2 Cl 3).

Compound 4b 1- (α-D-Lixofuranosyl) -2,5,6-trichlorobenzimidazole The procedure was as for compound 4a except that compound 3b (632 mg, 1.07 mmol) was used in place of compound 3a. Is the same as described. TLC (identical spots in solvent systems 1 and 2) and proton spectrum were identical to those obtained for compound 4a. Yield: 175 mg (76%), white foam. Melting point: 175-176 ° C. _{C 12 H 11 O 4 N 2} Cl 3 was calculated for HR
MS: M ^<+> , 351.9784. Found: 351.9773 (M ⁺ ). Analysis value (
_{C 12 H 11 O 4 N 2} Cl 3 · H 2 O) C, H, N.

Compound 5a 2-Bromo-5,6-dichloro-1- (α-L-lyxofuranosyl) benzimidazole In a three-necked round-bottomed flask, compound 3a (460 mg, 0.96 mmol) and dichloromethane (50 ml) were added. added. While stirring the mixture at room temperature, anhydrous hydrogen bromide was bubbled through the solution for 40 minutes, then vented for 90 minutes and then vented again to form a white precipitate. Hydrogen bromide was stopped again after 135 minutes and the mixture was stirred for a further 3 hours. At this point, NaHCO ₃ (saturated) was added slowly until gas evolution ceased. Next, the clear solution was washed with NaHCO ₃ (sat., 50 ml), brine (50 ml).
) And dried over magnesium sulfate. The solvent was distilled off and azeotroped with diethyl ether under reduced pressure to obtain a yellow glassy product. Rf = 0.80 (solvent system 1)
. _{^{1 H NMR (DMSO-d 6}} ): δ8.18 (s, 1H), 8.01 (s,
1H), 6.25 (d, 1H, J = 7.8 Hz), 5.97 (m, 1H), 5.
74 (m, 1H), 5.17 (m, 1H), 4.26 (m, 2H), 2.19 (
s, 3H), 2.03 (s, 3H), 1.97 (s, 3H). The yellow glassy product was then combined with a stirred solution of ethanol, MeOH and water (50 ml) (1: 1:
Dissolved in 1). Next, sodium carbonate (380 mg, 3.6 mmol) was added to the solution.
Was added. After 100 minutes, glacial acetic acid (0.5 ml) was added and the alcohol was distilled off under reduced pressure. An additional 25 ml of cold water was added and the mixture was filtered. The solid product was recrystallized from methanol / water and dried at 78 ° C. under reduced pressure for 2 days to give Compound 5a as white crystals.
94 mg were obtained. Rf = 0.06 (solvent system 5). Melting point: 178-179 [deg.] C. ¹ H
NMR (DMSO-d ₆ ): δ 8.00 (s, 1H), 7.91 (s, 1H),
5.96 (d, 1H, J = 8.1 Hz), 5.58 (d, 1H, J = 6.6 Hz)
, D ₂ O exchangeable), 5.29 (d, 1H, J = 4.3 Hz, D ₂ O exchangeable)
, 4.71 (m, 2H), 4.59 (m, 1H), 4.19 (m, 1H), 3.
65 (m, 2H). _{C 12 H 11 O 4 N 2} Cl 2 HRMS calculated for Br
: M ⁺ , 395.9279. Found: 395.9273 (M ⁺ ). Analysis _{(C 1 2 H 11 O 4} N 2 Cl 2 Br) C, H, N.

[0134]Compound 5b 2-bromo-5,6-dichloro-1- (α-D-lyxofuranosyl) benziimi
Except for using Compound 3b instead of Compound 3a, the procedure was similar to that for Compound 5a.
This is the same as described above. TLC (same spot in solvent system 1) and pro
The ton spectra were identical to those obtained for compound 5a. Yield: 255
mg (84%, 2 steps), white crystals. Melting point: 178-179 ° C. C₁₂H₁₁O ₄ N₂Cl₃HRMS calculated for Br: M⁺, 395.9279. Measured value
: 395.9261 (M⁺). Analytical value (C₁₂H₁₁O₄N₂Cl₃) C, H,
N.

Compound 6a 5,6-Dichloro-1- (α-L-lixofuranosyl) -2- (methylamino)
Compound 3a (480 mg, 1.00 mmol) and 33% methylamine / absolute ethanol (25 ml) were added to a 250 ml pressurized bottle of benzimidazole. Seal the container,
The reaction was stirred at room temperature for 16 hours. Next, the solvent was distilled off and azeotroped with hexane and diethyl ether under reduced pressure. The remaining solid was recrystallized twice from a mixture of methanol and water and dried at 78 ° C. under reduced pressure to give compound 6a as a white solid.
59 mg (72%) were obtained. Rf = 0.09 (solvent system 1). Melting point: 131-132
° C. ¹ H NMR (DMSO-d ₆ ): δ 7.40 (s, 1 H), 7.36 (s
, 1H), 6.81 (m, 1H, D ₂ O interchangeable), 5.73 (d, 1H, J =
8.1Hz), 5.27 (d, 1H , J = 4.4Hz, D 2 O exchangeable), 5.
24 (d, 1H, J = 4.3 Hz, D ₂ O exchangeable), 4.66 (t, 1H, J
= 5.6, D ₂ O exchangeable), 4.57 (m, 1H), 4.44 (m, 1H),
4.16 (m, 1H), 3.63 (m, 2H), 2.88 (d, 3H, J = 4.
40 Hz). Analysis _{(C 13 H 15 O 4 N} 3 Cl 2) C, H, N.

Compound 6b 5,6-Dichloro-1- (α-D-lyxofuranosyl) -2- (methylamino)
The procedure is the same as described for compound 6a, except that compound 3b was used instead of compound 3a. TLC (identical spot in solvent system 1) and proton spectrum were identical to those obtained for compound 6a. Yield: 233
mg (62%), white solid. Melting point: 126-128 [deg.] C. Analysis _{(C 13 H 15 O 4 N} 3 Cl 2) C, H, N.

Compound 7a 5,6-Dichloro-2-isopropylamino-1- (α-L-lyxofuranosyl) benzimidazole 1- (α-L-lyxofuranosyl) -2,5,6-trichlorobenzimidazole (compound 4a, After dissolving 300 mg (0.85 mmol) in ethanol (5 ml), isopropylamine (10 ml) was added. The flask was sealed and the reaction mixture was stirred at 70 C for 2 days. Next, the mixture was evaporated under reduced pressure, subjected to silica gel chromatography (3 × 25 cm) and eluted with solvent system 5. After evaporation of the solvent under reduced pressure, the solid product was stirred in 10 ml of benzene for 12 hours and collected by filtration.
The solid was dried under vacuum at 78 ° C. for 2 days and 202 mg of analytically pure compound 7a (
63%). Melting point: 198-201C. ¹ H NMR (DMSO-d ₆ ): δ
7.40 (s, 1H), 7.32 (s, 1H), 6.57 (bs, 1H, D ₂ O)
Exchangeable), 5.79 (m, 1H) , 5.28 (m, 1H, D 2 O exchangeable),
5.21 (m, 1H, D ₂ O exchangeable), 4.67 (bs, 2H, D ₂ O exchangeable), 4.54 (m, 1H), 4.42 (m, 1H), 4. 17 (m, 1H),
4.03 (m, 1H), 3.68 and 3.59 (m, 2H), 1.21 (bs
, 6H). Analysis _{(C 15 H 19 O 4 N} 3 Cl 2) C, H, N.

Compound 7b 5,6-Dichloro-2-isopropylamino-1- (α-D-lyxofuranosyl) benzimidazole The procedure was as described for compound 7a except that compound 4b was used instead of compound 4a. Is the same as TLC (identical spot in solvent system 1) and proton spectrum were identical to those obtained for compound 7a. Yield: 205
mg (64%), white solid. Melting point: 201-202 ° C. Analysis _{(C 15 H 19 O 4 N} 3 Cl 2) C, H, N.

Compound 8a 2-cyclopropylamino-5,6-dichloro-1- (α-L-lyxofuranosyl) benzimidazole Using cyclopropylamine instead of isopropylamine, compound 4a (300 mg, 0.80 mmol) was used. Except where used, the procedure is the same as described for compound 7a. Yield: 299 mg (65%), white solid. Melting point: 184-186C. ¹ H NMR (DMSO-d ₆ ): δ 7.47 (s, 1
H), 7.36 (s, 1H ), 7.05 (bs, 1H, D 2 O exchangeable), 5.
72 (m, 1H), 5.24 (m, 1H, D 2 O exchangeable), 5.17 (m, 1
H, D ₂ O exchangeable), 4.65 (bs, 2H, D ₂ O exchangeable), 4.53 (
m, 1H), 4.42 (m, 1H), 4.15 (m, 1H), 3.66 and 3
. 57 (m, 2H), 0.86 (m, 2H), 0.57 (m, 1H), 0.50
(M, 1H). Analysis _{(C 15 H 17 O 4 N} 3 Cl 2) C, H, N.

Compound 8b Cyclopropylamine was used instead of 2-cyclopropylamino-5,6-dichloro-1- (α-D-lyxofuranosyl) benzimidazole isopropylamine, and compound 4b (248 mg, 0 The procedure is the same as described for compound 7a, except that .66 mmol) was used. TLC (identical spot in solvent system 1) and proton spectrum were identical to those obtained for compound 8a. Yield: 247 mg (67%), white solid. Melting point: 183-185 [deg.] C. Analysis _{(C 15 H 17 O 4 N} 3 Cl 2) C, H, N.

Compound 9a 5,6-Dichloro-1- (α-L-lixofuranosyl) benzimidazole-2
-Thion Method A: A 500 ml round bottom flask equipped with a Claisen adapter and stirrer was evacuated and flushed with argon. Next, 5,6-trichlorobenzimidazole-2
-Thion (Compound 10, 1.53 g, 7.0 mmol) was added to CH ₃ CN (80 m
l). Bis (trimethylsilyl) acetamide (1.95 ml, 7.9
Mmol) was added dropwise via syringe and the mixture was heated (30-40 ° C) until the heterocycle was dissolved. Compound 2a (Kam, BL, Barascut, J.-L., Imbach, J.-L.
"A general method of synthesis and isolation of tetra-O-acetyl-D-aldopentofuranose, and a study by NMR spectroscopy (A General Method of Synthesis)
and Isolation, and an NMR-Spectroscopic Study, of Tetra-O-acetyl-Da
Ldopentofuranoses) "Carbohydrate Res. 1979, 69, see 135-142) (2. 5g, was added to a stirred solution of which 7.9 mmol) was dissolved in _CH 3 CN (40ml), immediately TMSOTf (1. (5 ml, 7.9 mmol). 24
After an hour, the solvent was distilled off under reduced pressure, and the remaining residue was subjected to silica gel chromatography (3.
X 25 cm) and eluted first with solvent system 4 and then with solvent system 3. Compound 1
Both 0 (40 mg) and the protected nucleoside (2.84 g, 87% based on heterocycle consumed) were obtained as separate compounds. Rf = 0.45
(Compound 10, solvent system 3). ¹ H NMR (DMSO-d ₆ ): δ 13.33 (
bs, 1H), 7.93 (s, 1H), 7.41 (s, 1H), 6.75 (d,
1H, J = 8.3 Hz), 6.13 (m, 1H), 5.74 (m, 1H), 5.
13 (m, 1H), 4.23 (m, 2H), 2.19 (s, 3H), 2.03 (
s, 3H), 1.94 (s, 3H).

The protected nucleoside (2.75 g, 5.66 mmol) was added to a 200 ml round bottom flask and dissolved in 92% ethanol / water (50 ml, v / v). Sodium carbonate (4.0 g, 37 mmol) was added to the stirred solution and the reaction mixture was stirred at room temperature for 24 hours. After adding acetic acid (2 ml), the ethanol was distilled off under reduced pressure. The resulting mixture was added to an additional 275 ml of cold water and EtOAc (15 × 50 ml) was added.
). Then, the solvent was distilled off under reduced pressure. The resulting solid was recrystallized from methanol and dried under reduced pressure at 78 ° C. for 2 days to obtain 1.48 g of 9a as white crystals (7
4%). Rf = 0.27 (solvent system 2). Melting point: 235-236 [deg.] C. ¹ H N
MR (DMSO-d ₆ ): δ 13.15 (bs, 1H, D ₂ O exchangeable, NH)
, 7.62 (s, 1H, H7 or H4), 7.40 (s, 1H, H4 or H
7), 6.46 (d, 1H, J = 8.2 Hz, H1 '), 5.31 (d, 1H,
J = 6.7 Hz, D ₂ O exchangeable, 2′-OH), 5.15 (d, 1H, J = 3
. 8 Hz, _{D 2} O exchangeable, 3'-OH), 4.81 ( m, 1H, H2 '), 4
. 67 (t, 1H, J = 4.1, 5'-OH), 4.67 (m, 1H, H4 ')
, 4.50 (m, 1H, H3 '), 3.61 (m, 2H, H5'a and H5'
b). Analysis _{(C 12 H 12 O 4 N} 2 Cl 2 S) C, H, N.

Method B: Compound 4a (42 mg, 0.12 mmol) in a 10 ml round bottom flask
Thiourea (36 mg, 0.48 mmol) and absolute ethanol (2 ml) were added. The reaction mixture was heated at reflux for 19 hours, the solvent was distilled off under reduced pressure, and the resulting residue was pulverized with 5 ml of water. After standing for 3 hours, the solid was filtered off and
For 48 hours under reduced pressure to obtain 30 mg (71%) of a white product. TLC (identical spot in solvent system 2) and proton spectrum were identical to those obtained for compound 9a (method A). Melting point: 234-236 ° C.

Compound 9b 5,6-dichloro-1- (α-D-lyxofuranosyl) benzimidazole-2
-Thion Instead of compound 2a, compound 2a (Kam, BL, Barascut, J.-L., Imbach,
J.-L. "A general method of synthesis and isolation of tetra-O-acetyl-D-aldopentofuranose, and a study by NMR spectrum analysis (A General Method of Syn.
thesis and Isolation, and an NMR-Spectroscopic Study, of Tetra-O-acet
yl-D-aldopentofuranoses) ", except that Carbohydrate Res. 1979, 69, 135-142) was used. The procedure is identical to that described for compound 9a (method A). TLC (identical spot in solvent system 2) and proton spectrum were identical to those obtained for compound 9a (methods A and B). The yield in the first step is 91% (based on the heterocycle consumed) and the yield in the second step is quantitative (2
. 0 g). Analytical samples were prepared by recrystallization from methanol and drying as in 9a. Melting point: 234-236 ° C. Analysis _{(C 12 H 1 2 O 4} N 2 Cl 2 S) C, H, N.

[0145]Compound 11a 2-benzylthio-5,6-dichloro-1- (α-L-lyxofuranosyl) ben
Compound 9a (351 mg, 1.0 mmol), H ₂ O (25 ml) and CH₃CN (15 ml) was added. To this suspension, add concentrated water
12 drops of ammonium oxide were added and dissolved. Next, benzyl bromide (0.12 m
1,1.0 mmol) was added and the mixture was stirred at room temperature for 16 hours. Then,
Excess acetonitrile was distilled off under reduced pressure, and the aqueous layer was extracted with EtOAc (2 × 40 ml).
Was. Combine the organic extracts and dry (MgSO 4)₄), The solvent is distilled off and a white solid
410 mg (93%) of the product were obtained. Next, this was recrystallized from methanol / water to give 7
After drying under reduced pressure at 8 ° C. for 2 days, 361 mg of compound 11a was obtained as a white crystalline product (
82%). Melting point: 210-212 ° C.¹1 H NMR (DMSO-d₆): Δ
7.89 (s, 1H), 7.78 (s, 1H), 7.37 (m, 5H), 5.8
0 (d, 1H, J = 7.9 Hz), 5.51 (d, 1H, J = 7.3 Hz, D₂ O exchangeable), 5.26 (d, 1H, J = 4.2 Hz, D₂O exchangeable), 4.
67 (t, 1H, J = 5.7), 4.62 (m, 3H), 4.50 (m, 1H)
, 4.15 (m, 1H), 3.60 (m, 2H). Analytical value (C₁₉H₁₈O₄N ₂ Cl₂S) C, H, N.

Compound 11b 2-benzylthio-5,6-dichloro-1- (α-D-lyxofuranosyl) benzimidazole The procedure was as described for compound 11a except that compound 9b was used in place of compound 9a. It is. TLC (identical spot in solvent system 1) and proton spectrum were identical to those obtained for compound 11a. Yield: 2
07 mg (47%), white crystalline product. Melting point: 196-198C. Analysis _{(C 1 9 H 18 O 4} N 2 Cl 2 S) C, H, N.

Compound 12a 5,6-Dichloro-1- (α-L-lyxofuranosyl) -2- (methylthio) benzimidazole Instead of benzyl bromide, methyl iodide (0.06 ml, 1.0 mmol) was used. Except for this, the procedure is identical to that described for compound 11a. Yield: 305 mg (84%) of compound 12a as a white crystalline product. Melting point: 210-
212 ° C. _{^{1 H NMR (DMSO-d 6}} ): δ7.86 (s, 1H), 7.7
7 (s, 1H), 5.80 (d, 1H, J = 8.1 Hz), 5.52 (d, 1H)
, J = 7.1 Hz, D ₂ O exchangeable), 5.28 (d, 1H, J = 3.6 Hz,
D ₂ O exchangeable), 4.70 (t, 1H, J = 5.6, D 2 O exchangeable), 4.
63 (m, 1H, H3 '), 4.52 (m, 1H), 4.17 (m, 1H), 3
. 63 (m, 2H). Analysis _{(C 13 H 14 O 4 N} 2 Cl 2 S) C, H, N.

Compound 12b 5,6-Dichloro-1- (α-D-lyxofuranosyl) -2- (methylthio) benzimidazole Instead of benzyl bromide, methyl iodide (0.06 ml, 1.0 mmol) was used. Except for this, the procedure is the same as described for compound 11b. TL
C (identical spot in solvent system 1) and proton spectra were identical to those obtained for compound 12a. Yield: 142 mg (39%), white crystalline product.
Melting point: 204-206 [deg.] C. Analysis _{(C 13 H 14 O 4 N} 2 Cl 2 S) C, H, N
.

Compound 14 2,3'-O-cyclo-5,6-dichloro-1- (β-L-lyxofuranosyl)
Benzimidazole triflic anhydride (trifluoromethanesulfonic anhydride, 0.3
7 ml, 2.2 mmol) dissolved in dichloromethane (4.5 ml).
2,5,6-Trichloro-1- (3 ′, 5′-di-O-benzoyl-β-L-lyxofuranosyl) benzimidazole (compound 13,820 mg, 1.5 mmol) was treated with dichloromethane (7.5 ml). Added to a solution of the mixture in pyridine (0.75 ml). The reaction mixture was stirred at 0 ° C. and monitored by TLC. Three
After 0 min, water (1.5 ml) was added and the temperature of the reaction mixture was raised to 40 ° C. One more
After stirring for 5 hours, the mixture was diluted with dichloromethane (10ml) and water (10ml). The organic extract was washed with water (5 ml), dried over anhydrous sodium sulfate,
Filter and evaporate the filtrate to dryness. The residue was subjected to silica gel chromatography (2
. 5 × 15 cm, eluent: methanol (0-2%) / dichloromethane gradient), one major compound (Rf: 0.40, 590 mg) was obtained as a foamy product. _{^{1 H NMR (DMSO-d 6}} ): δ7.9~7.5, (m,
12H, phenyl, H-4 and H-7), 6.61 (d, 1H, H-1 ', J
= 5.4 Hz), 6.27 (t, 1H, H-2 ', J = 5.5 Hz), 5.88
(T, 1H, H-3 ', J = 5.5 Hz), 4.9 (m, 1H, H-4'), 4
. 6 to 4.5 (m, 1H, H-5 '), 4.3 to 4.2 (m, 1H, H-5 ")
.

The foamy product was treated with a solution of ethanol and water (9: 1, volume / volume, 20 m
l) and sodium carbonate (0.45 g, 4.2 mmol) was added. After stirring the reaction mixture for 4 days, acetic acid (1 ml) was added and the mixture was evaporated to dryness. water(
10 ml) and ethyl acetate (20 ml) were added to the residue. The organic extract in water (
2 × 5 ml), dried over sodium sulfate, filtered and the filtrate was evaporated to dryness. The residue was suspended in boiling dichloromethane (10 ml) and methanol was added until completely dissolved. Compound 14 (200 mg, 43%) crystallized from this solution. Melting point: 255-257 ° C (decomposition). Rf: 0.18. ¹ H NMR (DMS
_O-d 6): δ7.96 and 7.62 (2s, 2H, H- 4 and H-7),
6.36 (d, 1H, OH-2 ', J = 2.9 Hz), 6.18 (d, 1H, H
-1 ', J = 4.0 Hz), 5.04 (t, 1H, H-3', J = 2.9 Hz)
, 5.01 (t, 1H, OH-5 '), J = 5.4 Hz), 4.7 (m, 1H,
H-2 '), 4.4 (m, 1H, H-4'), 3.5 to 3.4 (m, 1H, H-
5 '), 3.4~3.3 (m, 1H, H-5 "). Analysis _{(C 12 H 10 Cl 2 N} 2 O 4) C, H, N.

Compound 15 2-isopropylamino-5,6-dichloro-1- (β-L-lyxofuranosyl) benzimidazole Compound 14 (150 mg, 0.47 mmol) was added to ethanol (3.3 ml).
Was dissolved. Isopropylamine (2.0 ml, 24 mmol) was added, the flask was sealed and the reaction mixture was stirred at 70 C for 1 week. At this point, the reaction was
Checked by. Since only a partial reaction occurred, the reaction mixture was
Stirred at C for another week. The mixture was then evaporated to dryness and the residue was taken up in ethyl acetate (2
0 ml) and water (5 ml). The organic extract was washed with water (2 × 5 ml),
dried over a ₂ SO _4, filtered, and the filtrate was evaporated to dryness. The residue was chromatographed on silica gel (2.5 × 15 cm, eluent: methanol (6%) / dichloromethane). The fraction contained in the main spot (Rf: 0.24) was evaporated to dryness. The resulting solid was suspended in boiling dichloromethane (5 ml) and methanol was added until completely dissolved. Compound 15 (127 mg, 71%) crystallized from this solution. Rf: 0.24. Melting point: 197-199 [deg.] C. ¹ H NMR (DMSO
-D ₆ ): δ 7.60 and 7.31 (2s, 2H, H-4 and H-7), 7
. 21 (d, 1H, NH, J = 7.1 Hz), 6.02 (d, 1H, H-1 ′,
J = 6.6 Hz), 5.84 (bs, 1H, OH-3 ′, J = 2.9 Hz), 5
. 32 (d, 1H, OH-2 ', J = 5.9 Hz), 4.85 (t, 1H, OH
−5 ′, J = 4.9 Hz), 4.4 (m, 1H, H−2 ′), 4.2 (bs, 1
H, H-3 '), 4.0-3.9 (m, 1H, C H (CH 3) 2), 3.7~3
. 7 (m, 3H, H-4 ', H-5' and H-5 "), 1.18 (d, 6H,
_{CH (C H 3) 2,} j = 6.4Hz). Analysis _{(C 15 H 19 Cl 2 N} 3 O 4)
C, H, N.

[0152]

[Table 1]

D. Analysis of Antiviral Activity and Cytotoxicity Cell culture methods KB, BSC-1, and normal growth and culture of HFF cells were performed using Hanks's salt [MEM (MEM (10%)) supplemented with 10% bovine serum or 10% fetal bovine serum (HFF cells). H)] or a minimum essential medium (MEM) containing Earle's salt [MEM (E)]. The sodium bicarbonate concentration was varied to match the required buffer capacity. Cells were harvested with 0.05% trypsin + 0.02% EDTA / HEP
Using an ES buffered salt solution, the cells were cultured at a dilution ratio of 1: 2 to 1:10 according to a conventional method (Shipman, C. Jr., Smith, SH, Carlson, RH, Drach, JC "Simple Herpesvirus. Antiviral activity of arabinofuranosyl adenine and arabinofuranosyl hypoxanthine on infected KB cells I. Antiviral activity of Arabinofuranosylade in synchronized suspension culture
nine and Arabinofuranosylhypoxanthine in Herpes Simplex Virus-Infected K
B Cells.I.Selective Inhibition of Viral DNA Synthesis in Synchronized
Suspension Cultures) "Antimicrob. Agents Chemother. 1976, 9, 120-127).

The HCMV for virological method storage, as previously reported in detail, has a multiplicity of infection (moi.
) Was prepared by infecting HFF cells with <0.01 plaque forming units (pfu) / cell (Turk, SR, Shipman, C., Jr., Nassiri, MR, G
enzingler, G., Krawczyk, SH, Townsend, LB, Drach, JC "Pyrrolo [2,3-d] pyrimidine nucleosides as inhibitors of human cytomegalovirus
(Pyrrolo [2,3-d] pyrimidine Nucleosides as Inhibitors of Human Cytomegalov
irus) "Antimicrob. Agents Chemother. 1987, 31, 544-550). The high titer HSV-1 for storage is obtained from KB cells (ATCC), also as described above.
) For m. o. i. Was prepared by infection at <0.1 (Turk, SR,
Shipman, C., Jr., Nassiri, MR, Genzingler, G., Krawczyk, SH, Townsen
d, LB, Drach, JC "Pyrrolo [2,3-d] pyrimidine Nucleosides as an inhibitor of human cytomegalovirus
as Inhibitors of Human Cytomegalovirus) Antimicrob.Agents Chemother.
1987, 31, 544-550). Virus titers were determined as previously described by monolayer culture of HFF cells for HCMV and BS for HSV-1.
It was measured using a monolayer culture of C-1 cells (Prichard, MN, Turk, SR, Colema
n, LA, Engelhardt, SL, Shipman, C., Jr., Drach, JC "A Microtiter Virus Yield Assay for Evaluation of Antiviral Compounds Against Human Cytomegalovirus and Herpes Simplex Virus"
d Reduction Assay for the Evaluation of Antiviral Compounds Against Huma
n Cytomegalovirus and Herpes Simplex Virus) "J. Virol. Methods 1990, 28
, 101-106). Briefly, HFF or BSC-1 cells were transferred to 96-well cluster dishes as described above and incubated overnight at 37 ° C. The next day, the cultures were inoculated with HCMV or HSV-1 and serially diluted 1: 3 across the remaining 11 columns of a 96-well plate. After virus adsorption, the inoculum was replaced with fresh medium, and the culture was incubated with HSV for 7 days for HCMV.
-1 was incubated for 2-3 days. In wells with dilutions,
Plaque counts under 20x magnification resulted in 5-20 plaques per well. The virus titer was calculated by the formula: titer (pfu / ml) = number of plaques × 5 × 3 ^n, where n is the virus used to infect plaque-counted wells Represents the n th dilution.

HCMV Plaque Reduction Assay HFF cells in a 24-well cluster dish were harvested using the method described above for approximately 1 HCMV.
00p. f. u. / Cm ² . After virus adsorption, compounds dissolved in growth medium were added to duplicate wells at selected concentrations of 4-8. 7 ~ at 37 ℃
After 10 days of incubation, the cell sheets were fixed, stained with crystal violet, and plaques on the microscope were counted as described above. The effect of the drug was calculated as the percentage reduction in the presence of the respective drug concentration relative to the number of plaques seen in the absence of the drug.

HCMV Yield Assay HFF cells were transferred to 96-well cluster dishes as described above and incubated overnight to remove media, 0.5-1 p.m. as reported elsewhere. f. u.
/ Cell m. o. i. The cultures were inoculated with HCMV at (Prichard, MN, Turk,
SR, Coleman, LA, Engelhardt, SL, Shipman, C., Jr., Drach, JC "Microtiter virus yield reduction assay for the evaluation of antiviral compounds against human cytomegalovirus and herpes simplex virus (A Microtite
r Virus Yield Reduction Assay for the Evaluation of Antiviral Compounds
Against Human Cytomegalovirus and Herpes Simplex Virus) "J. Virol. Meth
ods 1990, 28, 101-106). After virus adsorption, the inoculum was replaced with 0.2 ml of fresh medium containing the test compound. The first row of 12 wells was not treated and was used as a virus control. An additional 0.1 ml of medium containing 3 times the desired final concentration of test compound was added to each well of the second row. The contents of the 12 wells were mixed by repeated aspiration with a pipette, then serially diluted 1: 3 across the remaining wells. In this way, six compounds could be tested in duplicate on a single plate at concentrations from 100 mM to 0.14 mM. The plates were incubated at 37 ° C. for 7 days, freeze-thawed for one cycle, and aliquots from each of the eight wells of a given column were transferred to the first column of a fresh 96-well monolayer culture of HFF cells. The contents were mixed and serially diluted 1: 3 across the remaining 11 columns of the second plate. Each column of the original first plate was diluted in this way across another plate. Cultures were incubated, plaques were counted and titers were calculated as described above.

HSV-1 ELISA HSV-1 was detected using an ELISA (Prichard, MN, Shipman, C.,
Jr. "A Three Dimensiona Model for Analyzing Drug-Drug Interaction"
l Model to Analyze Drug-Drug Interaction) Antiviral Res. 1990, 14, 181
-206). In a 96-well cluster dish, 10,000 BSC-1 cells / well in 200 μl / well of MEM (E) + 10% bovine serum were transferred.
After overnight incubation at 37 ° C., the four selected drug concentrations and HSV-1
100 p. f. u. / Well. After incubation at 37 ° C. for 3 days, the medium was removed, the plates were blocked, washed and horseradish peroxidase-conjugated rabbit anti-HSV-1 antibody was added. After removing the antibody containing solution, the plate is washed and then a solution of tetramethylbenzidine 15 as a substrate.
0 μl / well was added and developed. The reaction was stopped with H ₂ SO ₄ and the absorbance was 450
And 570 nm. The drug effect was calculated as the percentage decrease in absorbance in the presence of each drug concentration relative to the absorbance obtained with the virus in the absence of drug.

[0158]HHV-6 (ELISA) Enzyme-linked immunosorbent assay (ELISA) uses a covalent amine plate (c
ovalent amine plate) (Costar, Cambridge, Mass.).
The plate contains bis (sulfosuccinimidyl) subbing, a homobifunctional crosslinker.
After activation by adding a plate, the plate is washed with PBS. Suspended HSB2 cells 150μ
sample was incubated with the drug on a separate plate
Infect HHV-6 and solubilize in Triton X-100 in coating buffer. Pre
Cover the plate and 5% CO at 37 ° C₂Incubate for 1 hour in an atmosphere
You. These binding conditions facilitate the covalent attachment of the antigen to the free end of the crosslinker.
Was. After covalent binding, the antigen solution was decanted and the plates were washed with 0.05% Tween 20 (HB
(ST) containing HEPES-buffered saline six times (Shipman, C., Jr., “Tissue
4- (2-hydroxyethyl) -1-piperazineethanesul as culture buffer
Evaluation of 4- (2-Hydroxyethyl) -1-piperazine
ethane-sulfonic Acid (HEPES) as a Tissue Culture Buffer), Proc. Soc. E
xp. Biol. 1969, 130, 305-310), soak for 3 minutes for each wash
I did. Block unbound sites on the plate and decant blockers
Next, add a diluted primary monoclonal antibody specific for HHV-6 (GS).
The plate is then covered and incubated at 37 ° C. for 1 hour. plate
Wash again, add blocker again and label with horseradish peroxidase
The added rabbit anti-mouse antibody is added to each well. Plate at 37 ° C for 1 hour
Incubate again, wash as above, and develop for 30 minutes at room temperature using TMB-Turbo (Pierce, Rockford, IL). The reaction is 2MH ₂ SO₄Stop at Measure the absorbance of each well at 450/570 nm
I do.

HIV-1 This assay measures the abundance of HIV in the supernatant of CEM cells (ATCC) infected with the IIIB strain of HIV-1 by the amount of RV pickling. Reverse transcriptase (R
S) is used as a marker for HIV-1. The cells are grown, infected, and the compound to be analyzed is incubated in the presence of seven concentrations starting at 1 or 100 μM (two-fold log dilutions of 10). Procedures and RT assays are described in Kucera,
LS, Lyer, N., Puckett, SH, Buckheit, RW, Jr., Westbrook, L., Toyer,
BR, White, EL, Germany-Decker, JM, Shannon, WM, Chen, RCS, Na
ssiri, MRS, Shipman, C., Jr., Townsend, LB Drach, JC, "Triciribine and triciribine-5'- against human immunodeficiency virus types 1 and 2.
Activity of Triphosphate and Activity of Triciribine and Triciribine-5'-monoph
osphate Against Human Immunodeficiency Virus Types 1 and 2), AIDS Res.
Human Retviruses 1993, 9, 307-314; White, EL, Buckheit, RWJr., Ross
, LJ, Germany, JM, Andries, K., Pauwels, R., Janssen, PAJ, Shanno
n, WM, Chirigosm, MAA, "TIBO derivative R82913 is a potent inhibitor of HIV-1 reverse transcriptase with a heteropolymeric template, A TIBO Derivative, R
82913, is a Potent Inhibitor of HIV-1 Reverse Transcriptase with Heterop
olymer Templates) ", Antiviral Res. 1991, 16, 257-266.

Cytotoxicity Assay Routine cytotoxicity studies were performed using two different assays. (i) Cytotoxicity produced in quiescent HFF cells was determined by microscopic observation of cells not infected with the virus used in the plaque assay (Turk, SR, Shipman, C., Jr., Nass.
iri, MR, Genzingler, G., Krawczyk, SH, Townsend, LB, Drach, JC “Pyrrolo [2,3-d] pyrimidine nucleoside (Pyrrolo [2,3-d] pyrimidine as an inhibitor of human cytomegalovirus) Nucleosides as Inhibitors of Human
Cytomegalovirus) Antimicrob. Agents Chemother. 1987, 31, 544-550). (ii) The effect of the compound on doubling the number of KB cells between two individuals was measured by crystal violet staining as described above and the spectrophotometric quantification of the dye eluted from the stained cells (Prichard, MN, Prichard). , LE, Ba
guley, WA, Nassiri, MR, Shipman, C., Jr. “Three-Dimensional Analysis of the Synergic Cytotoxicity of Ganciclovir and Zidovudine.
gistic Cytotoxicity of Ganciclovir and Zidovudine) Antiviral Res. 1991
, 35, 1060-1065). Briefly, KB cells were added to a 96-well cluster dish at 3000-5000 cells / well. After overnight incubation at 37 ° C., test compounds were added in quadruplicate at 6-8 concentrations. Plate C
Incubate for 48 hours at 37 ° C. in an O ₂ incubator, wash, 9
The cells were fixed with 5% ethanol and stained with 0.1% crystal violet. Acidified ethanol was added and the plates were read at 570 nm on a spectrophotometer designed to read a 96-well ELISA assay plate.

Data Analysis A volume-response relationship was constructed by linearly regressing the percent inhibition of the parameters derived above against log drug concentration. 50% inhibitory concentration (IC50) or I
C90 was calculated from the regression line. Positive controls (Acyclovir for HSV-1, Ganciclovir for HCMV, and 2-acetylpyridinethiosemicarbazone for cytotoxicity) were used in all assays. HC
Antiviral activity data against MV (plaque and yield) and HSV-1 (ELISA), and cytotoxicity data (gross and growth) were recorded for many of the synthesized compounds. The data is summarized in Table 2. Antiviral activity data for another strain of HCMV was also recorded for many of the compounds synthesized. The data is summarized in Table 3.

[0162]

[Table 2]

[0163] ^a plaque and yield reduction assay was performed in duplicate as described in the text. Results from the plaque assay is described as IC _50, the result of yield reduction test is described as IC _90. ^b Plaque assay was used to measure the activity of DHPC against HSV-1, and all other compounds were analyzed by quadruplicate ELISA. ^c Visual cytotoxicity was measured on HFF cells at the time of HCMV plaque counting. The results of two experiments are shown. Inhibition of KB cell growth was measured as described in the text in four assays. Results are shown as _{IC 50.} ^d Mean values derived from 2-4 experiments. ^e > 100 indicates an IC ₅₀ or IC ₉₀ greater than the indicated (highest) concentration tested. ^f Mean value from 15 experiments ± standard deviation. ^g Mean ± SD from 108, 33 and 3 experiments, respectively.

[0164]

[Table 3]

[0165] ^a plaque and yield reduction assay was performed in duplicate as described in the text. Table 2 also shows data for the Towne strain. Results from the plaque assay is described as IC _50, the result of yield reduction test is described as IC _90. ^b Average value derived from 2-3 experiments.

The activity of compounds against hepatitis B virus (HBV) is described in Jansen, R., et al., "Antimicrobial Agents and Chemotherapy", Vol.
.37, No. 3, pp. 441-447, 1993. The IC ₅₀ for 2-bromo-5,6-dichloro-1- (α-L-lyxofuranosyl) benzimidazole (compound 5a) in two separate tests is 8.8 μM and 16 μM.
M.

Although the present invention has been described in detail with respect to specific embodiments thereof, it will be appreciated that various changes and modifications can be made without departing from the spirit and scope of the invention.
It will be clear to those skilled in the art.

[Procedural Amendment] Submission of translation of Article 34 Amendment of the Patent Cooperation Treaty

[Submission date] January 31, 2000 (2000.1.31)

[Procedure amendment 1]

[Document name to be amended] Statement

[Correction target item name] Claim 1

[Correction method] Change

[Correction contents]

Embedded image(In the above formula, R², R⁴, R⁵, R⁶And R⁷Are the same or different,
Independently -H, -F, -Cl, -Br, -I, -NO₂, -N (R⁸)₂, -OR⁸ , -SR¹²And -CF_ThreeIndependently selected from the group consisting of⁸Is independently -H or an alkyl group having 1 to 6 carbon atoms, ¹² Is independently -H or a hydrocarbyl group having from 1 to 10 carbon atoms;⁹, R^TenAnd R¹¹Are the same or different, and
Or a hydroxyl protecting group, wherein R⁴And R⁷Are both H, R⁵And R⁶Β is Cl
For the -D compound, R²Is a compound selected from the group consisting of: a compound having a formula selected from: anomeric, optical, and conformational isomers thereof, and pharmaceutically acceptable salts and prodrug derivatives thereof. -Or L-Lixofuranosylbenzimidazo
Compounds.

──────────────────────────────────────────────────続 き Continuation of front page (81) Designated country EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE ), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA, CH, CN, CU, CZ, DE, DK, EE, ES, FI, GB, GE, HU, IL, IS, JP, KE, KG, KP, KR, KZ, LC, LK , LR, LS, LT, LU, LV, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, UA, UG, US, UZ, VN, YU, ZW (71) Applicant Glaxo Group Limited GLAXO GROUP LIMITED UK Middlesex UB 60 NN Greenford Barclay Avenue Glaxo Welcome House (No address) Glaxo Wellcome House, Berkeley Avenue Greenford, Middlesex UB60NN, Great Britain (72) Inventors Leroy, Bee. Townsend, Michigan, United States, Ann, Arbor, East, Dobson, Place, 3317 (72) Inventor John C. Drachi Ann, Arbor, Barrister, Michigan, USA, 1372 (72) Inventor Karen, Kay. Byron, North Carolina, USA, Research, Triangle, Park, P.R. Oh. Box, 13398 Five, Moore, Drive (72) Inventor Frank, El. Boyd, Jr., North Carolina, United States, Research, Triangle, Park, P.E. Oh. Box, 13398 Five, Moore, Drive F-term (reference) 4C057 BB02 DD01 LL06 4C086 AA01 AA02 AA03 EA16 MA04 NA14 ZA75 ZB33

Claims (23)

[Claims] 1. The following formula:(In the above formula, R², R⁴, R⁵, R⁶And R⁷Are the same or different,
Independently -H, -F, -Cl, -Br, -I, -NO₂, -N (R⁸)₂, -OR ⁸ , -SR¹²And -CF_ThreeIndependently selected from the group consisting of⁸Is
R is independently -H or an alkyl group having 1 to 6 carbon atoms; ¹² Is independently -H or a hydrocarbyl group having from 1 to 10 carbon atoms;⁹, R^TenAnd R¹¹Are the same or different, and
Or a hydroxyl protecting group), anomeric, optical, and conformational isomers thereof, and pharmaceutically acceptable salts and prodrug derivatives thereof. D- or L-Lixofuranosylbenzimidazo
Compounds. It is wherein R ^2, -H, -F, -Cl, -Br, -I and -N (R ⁸⁾ is selected the group or al consisting of _2, R ⁴ and R ⁷ are both -H And wherein R ⁵ and R ⁶ are independently selected from the group consisting of —H, —F, —Cl, —Br, and —I. Zimidazole compounds. 3. The method according to claim 1, wherein the compound is an α-D-lyxofuranosylbenzimidazole compound.
The lyxofuranosylbenzimidazole compound according to claim 1 or 2. 4. The method according to claim 1, wherein the compound is a β-D-lyxofuranosylbenzimidazole compound.
The lyxofuranosylbenzimidazole compound according to claim 1 or 2. 5. The method according to claim 1, wherein the compound is an α-L-lyxofuranosylbenzimidazole compound.
The lyxofuranosylbenzimidazole compound according to claim 1 or 2. 6. The method according to claim 1, wherein the compound is a β-L-lyxofuranosylbenzimidazole compound.
The lyxofuranosylbenzimidazole compound according to claim 1 or 2. 7. 1- (Lixofuranosyl) -2,5,6-trichloro-benzimidazole,
1- (Lixofuranosyl) -2-bromo-5,6-dichloro-benzimidazole, 1- (Lixofuranosyl) -2-methylamino-5,6-dichloro-benzimidazole, 1- (Lixofuranosyl) -2-isopropylamino- 5,6-dichloro-benzimidazole, 1- (lixofuranosyl) -2-cyclopropylamino-5,6-dichloro-
Benzimidazole, 1- (Lixofuranosyl) -2-thio-5,6-dichloro-benzimidazole, 1- (Lixofuranosyl) -2-benzylthio-5,6-dichloro-benzimidazole, 1- (Lixofuranosyl) -2-methylthio The method according to claim 1, wherein the compound is selected from the group consisting of -5,6-dichloro-benzimidazole, anomeric, optical and conformational isomers thereof, and pharmaceutically acceptable salts and prodrug derivatives thereof. The lyxofuranosylbenzimidazole compound according to the above. 8. 1- (Lixofuranosyl) -2,5,6-trichloro-benzimidazole, its anomeric, optical, and conformational isomers, and pharmaceutically acceptable salts and prodrug derivatives thereof. The lixofuranosylbenzimidazole compound according to claim 1, which is selected from the group. 9. 1- (Lixofuranosyl) -2-bromo-5,6-dichloro-benzimidazole, its anomeric, optical and conformational isomers, and their pharmaceutically acceptable salts and prodrugs. The lyxofuranosylbenzimidazole compound according to claim 1, which is selected from the group consisting of: 10. 1- (Lixofuranosyl) -2-methylamino-5,6-dichloro-benzimidazole, its anomeric, optical, and conformational isomers, and their pharmaceutically acceptable salts and prodrug derivatives. The lixofuranosylbenzimidazole compound according to claim 1, which is selected from the group consisting of: 11. 1- (Lixofuranosyl) -2-isopropylamino-5,6-dichloro-benzimidazole, its anomeric, optical, and conformational isomers, and their pharmaceutically acceptable salts and prodrug derivatives. The lixofuranosylbenzimidazole compound according to claim 1, which is selected from the group consisting of: 12. 1- (Lixofuranosyl) -2-cyclopropylamino-5,6-dichloro-
The lixofuranosyl benzimidazole compound of claim 1, wherein the benzimidazole is selected from the group consisting of anomeric, optical, and conformers, and pharmaceutically acceptable salts and prodrug derivatives thereof. . 13. 1- (Lixofuranosyl) -2-thio-5,6-dichloro-benzimidazole, its anomeric, optical and conformational isomers, and their pharmaceutically acceptable salts and prodrug derivatives. The lyxofuranosylbenzimidazole compound according to claim 1, which is selected from the group consisting of: 14. 1- (Lixofuranosyl) -2-benzthio-5,6-dichloro-benzimidazole, its anomeric, optical and conformational isomers, and their pharmaceutically acceptable salts and prodrug derivatives. The lyxofuranosylbenzimidazole compound according to claim 1, which is selected from the group consisting of: 15. 1- (Lixofuranosyl) -2-methylthio-5,6-dichloro-benzimidazole, its anomeric, optical and conformational isomers, and their pharmaceutically acceptable salts and prodrug derivatives. The lyxofuranosylbenzimidazole compound according to claim 1, which is selected from the group consisting of: 16. A composition comprising a biologically acceptable carrier and a D- or L-lyxofuranosylbenzimidazole compound according to any one of claims 1 to 15. 17. A method for preventing the growth and / or replication of a virus in a cell infected with a virus, wherein the cell is a D- or L- according to any one of claims 1 to 15.
A method comprising contacting with an effective amount of a Lixofuranosylbenzimidazole compound to prevent virus growth and / or replication in cells. 18. A method for preventing viral infection in a cell, comprising the steps of:
A method comprising contacting a prophylactically effective amount of a D- or L-lyxofuranosylbenzimidazole compound according to any one of claims 1 to 4. 19. A method for treating a viral infection, comprising administering to a infected host a therapeutically effective amount of a D- or L-lyxofuranosylbenzimidazole compound according to any one of claims 1 to 15. Administering to the subject. 20. A method for preventing viral infection in a host, comprising administering to the host a prophylactically effective amount of a D- or L-lyxofuranosylbenzimidazole compound according to any one of claims 1 to 15. Administering to the subject. 21. The method according to any one of claims 17 to 20, wherein the viral infection is selected from the group consisting of HCMV, HSV and hepatitis virus infection. 22. The method according to any one of claims 17 to 20, wherein the viral infection is a hepatitis virus infection. 23. (a) reacting a compound of the following formula (II) with a compound of the following formula (III):
Process(In the above formula, R²Is selected from the group consisting of -Cl, -Br and = S;⁹, R ^Ten Or R¹¹Are independently the same or different and are -H or
(B) then performing one or more of the following steps (i) to (viii): (i) from the product of (a) one or more hydroxyl protecting groups are present in case of
(Ii) reacting the product of (a) with HX, wherein X is selected from the group consisting of -Cl, -Br, -F and -I, and (iii) ( The product of a) is⁸NH₂(Where R⁸Is -H or 1-6
A linear, branched or cyclic alkyl group having 2 carbon atoms)
 (iv) converting the product of (a) to H₂NCSNH₂(V) The product of (a) is converted to C₆H₅CH₂X (where X is selected from the group consisting of -Cl, -Br, -F and -I), (vi) reacting the product of (b) (iv) with C₆H₅CH₂X (wherein X is -Cl, -Br,
(Vii) reacting the product of (a) with CH_Three(Viii) reacting the product of (b) (iv) with CH_ThreeThe D- or L-lyxofuranosylbenzimidida according to claim 1, which is reacted with I.
A method for producing a sol compound.